迷走神经刺激后处理对大鼠在体心肌缺血—再灌注损伤的保护作用及机制的实验研究
|
摘要
背景
研究表明,在急性心肌缺血恢复血流灌注后,由缺血-再灌注损伤(ischemia reperfusion injury, IRI)所致的心肌梗死后死亡率仍然高达10%。动物实验亦发现,心肌缺血时高达50%的最终心肌梗死面积是归因于IRI。目前,已经公认缺血预处理是最为强大的内源性心肌保护干预措施。然而,由于心肌缺血事件的不可预测性,所以在临床实践中很难对其采取预先干预措施。因此,除了能够在实施心脏手术的患者选择性应用之外,缺血预处理的临床应用价值十分有限。缺血后处理则解决了临床干预时机选择的问题,而且其也已被证明具有确切的心肌保护作用。但是,诸如反复阻塞冠状动脉这样的操作有导致病变冠状动脉破裂或粥样斑块脱落等并发症的高度风险,故其临床应用价值也十分有限。相比之下,肢体远隔缺血后处理则能够避免在心脏直接进行操作,而且大量研究表明其对心肌IRI具有明确的保护作用。此外,肢体远隔缺血后处理还具有安全、实施简单和费用低廉等优点。因此,肢体远隔缺血后处理不失为临床治疗心肌IRI的一种较佳选择。
现已明确,炎症反应在心肌IRI的发生和发展过程中发挥着极为重要的致病作用,并且调节炎症反应可以减轻心肌IRI。晚近研究发现,迷走神经同样具有免疫炎症调节功能,其激活后能够通过胆碱能抗炎通路(cholinergic anti-inflammatory pathway)而实现对炎症反应的调控。在内毒素血症、结肠炎、风湿性关节炎和IRI等炎症性疾病时,迷走神经刺激能够通过抑制炎症细胞募集和炎症细胞因子释放而调控炎症反应,进而发挥其保护作用。虽然已经证实迷走神经刺激能够减小IRI所致的心肌梗死面积,但是目前尚无研究系统观察迷走神经刺激后处理对心肌缺血-再灌注损伤时心肌局部与全身炎症反应的影响。
联合应用不同的干预措施以获得有益的强效心肌保护效果一直是心肌IRI保护研究领域的重要方向,而且迷走神经刺激后处理和肢体远隔缺血后处理是两种作用机制明显不同的心肌保护干预措施。因此,我们设计了这个随机对照实验,主要目的包括：①观察迷走神经刺激后处理对心肌IRI保护的有效性、可用性和最佳干预时间；②评价将迷走神经刺激后处理和肢体远隔缺血后处理这两种极具临床应用前景的简单干预措施联合应用能否获得有益的协同性心肌保护作用；③观察PI3K/Akt和JAK/STAT信号转导通路在迷走神经刺激后处理、肢体远隔缺血后处理、联合应用迷走神经刺激后处理和肢体远隔缺血后处理心肌保护作用中的地位,以探索不同心肌保护干预措施的内在作用机制。本实验分为三个部分：
第1部分：迷走神经刺激后处理对心肌缺血-再灌注损伤的保护作用及其最佳干预时间的研究
第1部分实验的目的是采用大鼠在体心肌IRI模型比较性观察在不同时间点应用迷走神经刺激后处理对心肌IRI及其炎症反应的影响,以确定迷走神经刺激后处理的心肌保护作用及其最佳干预时间。
将140只体重290～320g的成年雄性Sprague Dawley (SD)大鼠麻醉后随机平均分为七组(每组20只)：空白对照组(S组)；对照组(C组)；缺血预处理组(IPC组)；心肌缺血15min迷走神经刺激后处理组(POESI15组)；再灌注前迷走神经刺激后处理组(POESRO组)；再灌注30min迷走神经刺激后处理组处理组(POESR30组)；再灌注60min迷走神经刺激后处理组(POESR60组)。所有大鼠开胸后采用丝线将其冠状动脉左前降支(left anterior descending coronary artery, LAD)套扎做成活结。除S组之外,所用大鼠均接受局部心肌缺血30min(阻断LAD)和再灌注120min(开放LAD)的处理。C组不采用任何其他干预措施；IPC组在结扎LAD前进行3个循环的缺血预处理,每个循环是由5min的LAD阻断和5min的LAD开放组成,总处理时间是30min; POESI15、POESR0、POESR30和POESR60组是分别在心肌缺血15min时、心肌再灌注前即刻、心肌再灌注30min时和心肌再灌注60min时对大鼠的右侧迷走神经进行电刺激,持续时间为30min。实验过程中,连续监测心率(heart rate, HR)、平均动脉压(mean arterial pressure, MAP)和Ⅱ导联心电图(electrocardiogram, ECG),并保持大鼠直肠温度在36.5～37.5℃之间。然后,将每组大鼠进一步随机平均分为2个亚组(每亚组10只),第1亚组在再灌注30min、60min和120min时抽取血液标本,采用大鼠专用试剂盒分别测定血清心肌肌钙蛋白I (cardiac troponin-I, cTnI)、肌酸激酶心肌型同工酶(myocardial-bound creatine kinase, CK-MB)、肿瘤坏死因子-α(tumor necrosis factor-α, TNF-α)、高迁移率组蛋白1(high mobility group box1protein, HMGB1)、细胞间粘附分子1(intercellular adhesion molecule1, ICAM1)、白介素-1(interleukin-1, IL-1)、白介素-6(interleukin-6, IL-6)和白介素-10(interleukin-10, IL-10)的浓度；在实验结束时,采用伊文思蓝和氯化三苯基四氮唑双重染色技术检测心肌梗死面积(infarct size, IS%)。在实验结束时,第2亚组用于检测缺血区心肌组织和非缺血区心肌组织TNF-α、HMGB1、ICAM1、IL-1、IL-6和IL-10的含量。
结果显示,各组大鼠的一般情况和心肌缺血前血流动力学参数的基础值比较差异无显著统计学意义。
与S组、C组或IPC组相比,POESI15组的HR在缺血期和再灌注期间均明显降低,POESRO组、POESR30组和POESR60组的HR在再灌注期间明显降低。与S组相比,C组、IPC组、POESI15组、POESRO组、POESR30组和POESR60组在缺血期和再灌注期的MAP和心率血压乘积(rate-pressure product, RPP)均明显降低。与IPC组相比,C组、POESI15组、POESRO组、POESR30组和POESR60组缺血期发生室性心律失常的大鼠数目明显增多,而且缺血期室性心律失常评分亦明显增高。与C组相比,IPC组、POESI15组和POESRO组再灌注初期发生室性心动过速(ventricular tachycardia, VT)的大鼠数目明显减少,而且再灌注初期室性心律失常评分亦明显降低。
与C组相比,IPC组、POESI15组、POESRO组、POESR30组和POESR60组的IS%值、血清cTnI和CK-MB浓度均明显降低；与IPC组相比,POESI15组、POESRO组.POESR30组和POESR60组的IS%值均明显增高；与POESI15组相比,POESR60组的IS%值、血清cTnI、CK-MB浓度明显增高,POESRO组和POESR30组的IS%值、血清cTnI和CK-MB浓度无显著统计学差异；与POESRO组相比,POESR60组的IS%值、血清cTnI和CK-MB浓度明显增高,POESR30组的IS%值、血清cTnI和CK-MB浓度无显著统计学差异；与POESR30组相比,POESR60组的IS%值、血清CK-MB浓度无显著统计学差异。
与S组相比,C组再灌注30min、60min和120min时血清TNF-a浓度明显增高；C组、IPC组和POESI15组再灌注60min时血清HMGB1浓度,C组、POESRO组、POESR30组和POESR60组再灌注120min时血清HMGB1浓度明显增高；C组、POESI15组、POESRO组、POESR30组和POESR60组再灌注120min时血清ICAM1浓度明显增高；C组、IPC组、POESRO组、POESR30组和POESR60组再灌注120min时血清IL-1的浓度明显增高；C组、IPC组、POESR30组和POESR60组再灌注120mmin时血清IL-6浓度明显增高；POESI15组再灌注120min时血清IL-10浓度明显增高。与C组相比,IPC组和POESI15组再灌注30min和60min时血清TNF-a浓度明显降低；IPC组、POESI15组、POESRO组、POESR30组和POESR60组再灌注120min时血清TNF-α、HMGB1、ICAM1、IL-1、IL-6浓度明显降低。与IPC组相比,POESI15组再灌注60mmin时血清TNF-a浓度明显增高；POESR60组再灌注120min时血清TNF-a浓度明显增高；POESRO组、POESR30组和POESR60组再灌注120min时血清HMGB1和ICAM1浓度明显增高;POESI15组再灌注120mmin时血清IL-1的浓度明显降低；POESI15组和POESRO组再灌注120min时血清IL-6浓度明显降低。与POESI15组相比,POESRO组、POESR30组和POESR60组再灌注120min时血清HMGB1和ICAM1的浓度明显增高；POESR60组再灌注120min时血清IL-1、IL-6和TNF-a的浓度明显增高。与POESRO组相比,POESR60组再灌注120min时血清HMGB1、IL-6和TNF-a的浓度明显增同；POESR30组和POESR60组再灌注120min时血清ICAM1浓度明显增高。与POESR30组相比,POESR60组再灌注120min时血清HMGB1、ICAM1和TNF-α浓度明显增高。
与S组相比,C组缺血区心肌组织TNF-α和HMGB1含量明显增高,IPC组缺血区心肌组织TNF-α含量明显降低；C组和POESR60组非缺血区心肌组织TNF-a含量明显增高；C组非缺血区心肌组织HMGB1含量明显增高,IPC组、POESI15组、POESRO组和POESR30组非缺血区心肌组织HMGB1含量明显降低；C组、POESI15组、POESRO组、POESR30组和POESR60组缺血区心肌组织ICAM1、IL-1和IL-6含量明显增高；C组和POESR60组非缺血区心肌组织ICAM1和IL-6含量明显增高,IPC组、POESI15组和POESRO组非缺血区心肌组织ICAM1含量明显降低；C组、IPC组、POESI15组、POESRO组、POESR30组和POESR60组非缺血区心肌组织IL-1含量、缺血区心肌组织和非缺血区心肌组织IL-10含量明显增高；IPC组和POESI15组非缺血区心肌组织IL-6含量明显降低。与C组相比,IPC组、POESI15组、POESRO组、POESR30组和POESR60组缺血区心肌组织和非缺血区心肌组织TNF-α、HMGB1、IL-1和IL-6含量明显降低；POESI15组缺血区心肌组织和非缺血区心肌组织IL-10含量明显增高。与IPC组相比,POESI15组、POESRO组、POESR30组和POESR60组缺血区心肌组织TNF-a含量明显增高；POESI15组非缺血区心肌组织HMGB1含量明显降低,POESR60组非缺血区心肌组织HMGB1含量明显增高；POESI15组、POESRO组、POESR30组和POESR60组缺血区心肌组织ICAM1含量明显增高；POESR30组和POESR60组非缺血区心肌组织ICAM1、缺血区IL-6含量明显增高；POESRO组、POESR30组和POESR60组缺血区心肌组织和非缺血区心肌组织IL-1、非缺血区心肌组织IL-6含量明显增高。与POESI15组相比,POESR30组和POESR60组缺血区心肌组织和非缺血区心肌组织TNF-a含量、非缺血区心肌组织ICAM1含量、缺血区心肌组织IL-1含量明显增高；POESR60组缺血区心肌组织HMGB1、IL-6含量明显增高,缺血区心肌组织和非缺血区心肌组织IL-10含量明显降低；POESRO组、POESR30组和POESR60组缺血区心肌组织ICAM1含量、非缺血区心肌组织HMGB1、IL-1和IL-6含量明显增高。与POESRO组相比,POESR60组缺血区心肌组织TNF-α、HMGB1、IL-1、IL-6含量、非缺血区心肌组织HMGB1、IL-1和IL-6含量明显增高；POESR30组和POESR60组缺血区心肌组织和非缺血区心肌组织ICAM1含量明显增高。与POESR30组相比,POESR60组缺血区心肌组织和非缺血区心肌组织ICAM1和IL-6含量以及非缺血区心肌组织HMGB1含量均明显增高。
第2部分：联合应用迷走神经刺激后处理和肢体远隔缺血后处理对心肌缺血-再灌注损伤保护作用的研究
根据第1部分实验的结果,在确定迷走神经刺激后处理最佳干预时间的基础上我们设计了这部分实验,其目的是评价联合应用迷走神经刺激后处理和肢体远隔缺血后处理能否获得增强的心肌保护作用。
将120只体重290-320g的成年雄性SD大鼠麻醉后随机平均分为六组(每组20只)：空白对照组(S组)；对照组(C组)；缺血预处理组(IPC组)；迷走神经刺激后处理组(POES组)；肢体远隔缺血后处理组(LRIPOC组)；联合应用迷走神经刺激后处理和肢体远隔缺血后处理组(POES-LRIPOC组)。C组和IPC组的处理同第1部分实验；POES组是根据第1部分实验获得的结果在最佳时间点进行迷走神经刺激；LRIPOC组的基本处理与C组相同,在心肌缺血20min时采用止血带结扎大鼠双侧后肢造成双后肢缺血10mmin,并在开放LAD实施心肌血流再灌注的同时开放后肢血流灌注；POES-LRIPOC组的基本处理与C组相同,迷走神经刺激后处理的实施方法同POES组,肢体远隔缺血后处理的实施方法同LRIPOC组。然后,将每组大鼠进一步随机平均分为2个亚组(每亚组10只),各组检测项目与第1部分实验相同。
结果显示,各组大鼠的一般情况和心肌缺血前血流动力学参数的基础值比较差异无显著统计学意义。
与S组、C组或IPC组相比,POES组和POES-LRIPOC组的HR在缺血期和再灌注期明显降低。与S组相比,C组、IPC组、POES组、LRIPOC组和POES-LRIPOC组的MAP和RPP在缺血期和再灌注期均明显降低。与IPC组相比,C组、POES组、LRIPOC组和POES-LRIPOC组缺血期室性心律失常发生率和室性心律失常评分明显增高。与C组相比,IPC组、POES组、LRIPOC组和POES-LRIPOC组再灌注期室性心律失常发生率和室性心律失常评分均明显降低；与LRIPOC组相比,IPC组、POES组和POES-LRIPOC组再灌注期间室性心律失常发生率和室性心律失常评分明显降低。
与C组相比,IPC组、POES组、LRIPOC组和POES-LRIPOC组的IS%值、血清cTnI和CK-MB浓度均明显降低；与IPC组或POES-LRIPOC组相比,POES组和LRIPOC组的IS%值明显增高；与POES组相比,LRIPOC组的IS%值和血清cTnl浓度明显增高,LRIPOC组的血清CK-MB浓度明显降低。与LRIPOC组相比,IPC组和POES-LRIPOC组的血清cTnI和CK-MB浓度均明显降低。
与S组相比,C组和LRIPOC组再灌注30min时血清TNF-a浓度明显增高；C组再灌注60min和120min时血清TNF-a浓度明显增高,IPC组和POES-LRIPOC组再灌注60min时血清TNF-a浓度明显降低；IPC组、POES组、LRIPOC组和POES-LRIPOC组再灌注120min时血清TNF-a浓度明显降低；C组、IPC组、POES组、LRIPOC组和POES-LRIPOC组再灌注60min时血清HMGB1浓度明显增高；C组和LRIPOC组再灌注120min时血清HMGB1浓度明显增高；C组、POES组和LRIPOC组再灌注120min时血清ICAM1浓度明显增高；C组、IPC组和LRIPOC组再灌注120min时血清IL-1和IL-6浓度明显增高；POES组和POES-LRIPOC组再灌注120min时血清IL-10浓度明显增高。与C组相比,IPC组、POES组、LRIPOC组和POES-LRIPOC组再灌注30min、60min和120min时血清TNF-a浓度、再灌注120min时血清HMGB1、ICAM1、IL-1、IL-6浓度明显降低；IPC组再灌注60min时血清HMGB1浓度明显降低；POES-LRIPOC组再灌注120min时血清IL-10浓度明显增高。与IPC组相比,POES组和LRIPOC组再灌注60min时血清TNF-a浓度明显增高；LRIPOC组再灌注120min时血清HMGB1和ICAM1浓度明显增高；POES组和POES-LRIPOC组再灌注120min时血清IL-1和IL-6浓度明显降低。与POES组相比,LRIPOC组再灌注60min时血清TNF-a浓度、再灌注120min时血清HMGB1、ICAM1、IL-1和IL-6浓度明显增高；POES-LRIPOC组再灌注120min时血清ICAM1浓度明显降低。与LRIPOC组相比,POES-LRIPOC组再灌注30min、60min和120min时血清TNF-a浓度、再灌注120min时血清HMGB1、ICAM1、IL-1和IL-6浓度均明显降低。
与S组相比,C组缺血区心肌组织TNF-a和HMGB1含量以及非缺血区心肌组织TNF-α、HMGB1和ICAM1含量明显增高；IPC组和POES-LRIPOC组缺血区心肌组织TNF-a含量明显降低；IPC组、POES组、LRIPOC组和POES-LRIPOC组非缺血区心肌组织HMGB1含量明显降低；C组、POES组、LRIPOC组和POES-LRIPOC组缺血区心肌组织ICAM1含量明显增高；IPC组、POES组和POES-LRIPOC组非缺血区心肌组织ICAM1和IL-6含量明显降低；C组、POES组和LRIPOC组缺血区心肌组织IL-1和IL-6含量明显增高；C组、IPC组、POES组、LRIPOC组和POES-LRIPOC组非缺血区心肌组织IL-1、IL-10含量、缺血区心肌组织IL-10含量明显增高；C组和LRIPOC组非缺血区心肌组织IL-6含量明显增高。与C组相比,IPC组、POES组、LRIPOC组和POES-LRIPOC组缺血区心肌组织和非缺血区心肌组织TNF-α、HMGB1、ICAM1、IL-1和IL-6含量均明显降低；POES组和POES-LRIPOC组缺血区心肌组织和非缺血区心肌组织IL-10含量明显增高。与IPC组相比,POES组和LRIPOC组缺血区心肌组织TNF-α、ICAM1和IL-1含量明显增高；POES-LRIPOC组缺血区心肌组织HMGB1含量明显降低,缺血区心肌组织和非缺血区心肌组织IL-10含量明显增高；POES组和POES-LRIPOC组非缺血区心肌组织HMGB1含量明显降低；LRIPOC组非缺血区心肌组织ICAM1、IL-1和IL-6含量,缺血区心肌组织IL-6含量明显增高。与POES组相比,POES-LRIPOC组缺血区心肌组织TNF-α、ICAM1和IL-1含量明显降低,非缺血区心肌组织IL-10含量明显增高；LRIPOC组非缺血区心肌组织HMGB1、ICAM1、IL-1和IL-6含量以及缺血区心肌组织ICAM1、IL-1和IL-6含量明显增高,缺血区心肌组织IL-10含量明显降低。与LRIPOC组相比,POES-LRIPOC组缺血区心肌组织TNF-α、ICAM1、IL-1和IL-6含量以及非缺血区心肌组织HMGB1、ICAM1、IL-1和IL-6含量明显降低,缺血区心肌组织和非缺血区心肌组织IL-10含量明显增高。
第3部分:PI3K/Akt和JAK/STAT信号转导通路在迷走神经刺激后处理以及联合应用迷走神经刺激后处理和肢体远隔缺血后处理心肌保护作用机制中地位的研究
本部分实验的目的是探讨PI3K/Akt和JAK/STAT信号转导通路在单独应用迷走神经刺激后处理以及联合应用迷走神经刺激后处理和肢体远隔缺血后处理心肌保护作用机制中的地位。
将20只体重290-320g的成年雄性SD大鼠麻醉后随机平均分为四组(每组5只)：对照组(C组)；迷走神经刺激后处理组(POES组)；肢体远隔缺血后处理组(LRIPOC组)；联合应用迷走神经刺激后处理和肢体远隔缺血后处理组(POES-LRIPOC组)。各组的处理基本同本实验第二部分,但是在开放LAD实施再灌注60min时结束实验,分别取大鼠左心室缺血区心肌标本和右心室非缺血区心肌标本。从缺血与非缺血区心肌标本中提取总蛋白和总RNA,采用实时定量聚合酶链反应(Real-time quantitative polymerase chain reaction, RQ-PCR)技术观察Akt和STAT3基因mRNA在缺血区心肌组织和非缺血区心肌组织的表达情况,并通过免疫蛋白印迹分析(Western-blotting)技术观察缺血区心肌组织和非缺血区心肌组织Akt和STAT3蛋白磷酸化的情况。
RQ-PCR结果显示,与C组相比,POES-LRIPOC组缺血区心肌组织和非缺血区心肌组织Akt基因和STAT3基因mRNA表达均明显增强；与POES组相比,POES-LRIPOC组缺血区心肌组织和非缺血区心肌组织Akt基因和STAT3基因mRNA表达明显增强；与LRIPOC组相比,POES-LRIPOC组缺血区心肌组织和非缺血区心肌组织Akt基因和STAT3基因mRNA表达明显增强。
Western-blotting结果显示,与C组相比,POES组、LRIPOC组和POES-LRIPOC组的缺血区心肌组织和非缺血区心肌组织p-Akt蛋白和p-STAT3蛋白的灰度值明显增加；与POES组相比,POES-LRIPOC组的缺血区心肌组织和非缺血区心肌组织p-Akt蛋白和p-STAT3蛋白的灰度值明显增加；与LRIPOC组相比,POES-LRIPOC组的缺血区心肌组织和非缺血区心肌组织p-Akt蛋白和p-STAT3蛋白的灰度值明显增加。
结论
通过本实验,我们得出以下结论：
1.心肌缺血15min时、再灌注前即刻、再灌注30mmin和再灌注60min时实施迷走神经刺激后处理均能够明显减小IRI所致的心肌梗死面积,并明显降低血清cTnI和CK-MB浓度,其中以在再灌注60min实施迷走神经刺激后处理的心肌保护效果最差,以在心肌缺血15mmin时实施迷走神经刺激后处理的心肌保护效果最强,但是迷走神经刺激后处理的心肌保护作用弱于缺血预处理。
2.缺血预处理、缺血期和再灌注期不同时间点进行迷走神经刺激后处理均能明显抑制再灌注期室性心律失常的发生；缺血15min时实施迷走神经刺激后处理抑制再灌注期心律失常的作用较其他时间点进行迷走神经刺激后处理更强。
3.联合应用迷走神经刺激后处理和肢体远隔缺血后处理能够获得更强的心肌保护作用,并且该心肌保护作用与缺血预处理的心肌保护作用几无差异。
4.缺血预处理、缺血期和再灌注期不同时间点进行迷走神经刺激后处理、肢体远隔缺血后处理、联合应用迷走神经刺激后处理和肢体远隔缺血后处理均能通过抑制心肌IRI过程中的炎症反应而发挥心肌保护作用。
5. PI3K/Akt和JAK/STAT信号转导通路相关基因在转录后蛋白磷酸化水平的上调参与了迷走神经刺激后处理和肢体远隔缺血后处理的心肌保护作用；而PI3K/Akt和JAK/STAT信号转导通路相关基因mRNA水平的上调则参与了联合应用迷走神经刺激后处理和肢体远隔缺血后处理的心肌保护。同时,联合应用迷走神经刺激后处理和肢体远隔缺血后处理的心肌保护作用机制可能还涉及了PI3K/Akt和JAK/STAT信号转导通路蛋白磷酸化水平的上调。
Background
Studies have shown that the mortality rate attributed to myocardial ischemia reperfusion injury (IRI) is still up to10%after prompt restoration of blood flow in the infarct-related coronary. In addition, many animal researches have shown that the IRI is responsible for up to50%of the final infarct size during acute myocardial ischemia. Although the ischemic preconditioning (IPC) remains the most powerful cardioprotective measure, its clinical application has been hampered by the requirement of intervention before onset of acute myocardial ischemia, which is clearly impossible in the setting of acute myocardial infarction. Ischemic postconditioning (IPOC) can be triggered during the clinically applicable period of myocardial reperfusion, which has already been shown cardioprotective. However, it can cause dangerous complications including rupture of diseased coronary artery and fall off of atheromatous plaque, which attribute to the requirement of repeated occlusion of coronary artery. Thus, the clinical application of IPOC is quite limited too. In contrast, limb remote ischemic postconditioning (LRIPOC) can be operated away from the heart and it has definitely cardioprotective effects. In addition, LRIPOC is easy to operate, safe and low-cost. As a result, LRIPOC is really a good choice to treat myocardial IRI.
Endogenous inflammatory response is a key factor in formation and progression of myocardial IRI. Recently, the immunoregulation of vagus nerve has been demonstrated, which can modulate inflammation by the cholinergic anti-inflammatory pathway when activated. During inflammatory diseases such as endotoxemia, colonitis, rheumatic arthritis and IRI, vagus nerve stimulation can provide protection by inhibiting inflammatory cells recruitment and inflammatory cytokines release. Moreover, it has been demonstrated that vagus nerve stimulation can reduce the infarct size caused by myocardial IRI. However, there has been no research observing the effects of vagus nerve stimulation postconditioning (POES) on local myocardial and systemic inflammation during myocardial IRI.
Combining different interventions to obtain an augmented cardioprotection is always one of the most popular research focuses in the area of myocardial IRI. Obviously, POES and LRIPOC might be triggered by different mechanisms. As a result, this randomized, controlled animal experimental study was designed and the aims of the present study were:1) to investigate the validity, usability and optimal intervention time of cardioprotection provided by vagus nerve stimulation postconditioning during myocardial IRI;2) to determine whether there was a synergistic cardioprotection by combination of POES and LRIPOC;3) to assess roles of both PI3K/Akt and JAK/STAT signal pathways in the cardioprotection of combined POES and LRIPOC, in order to explore the inherent mechanism of the interaction between POES and LEIPOC. This study was divided into three parts.
Part1Experimental study on cardioprotective and anti-inflammatory effects and optimal intervention time of vagus nerve stimulation postconditioning in rat with myocardial ischemia reperfusion injury in vivo
In this part of the experiment, an in vivo rat model of myocardial IRI was used to compare the cardioprotections and anti-inflammatory effects of vagus nerve stimulation postconditioning at different time points, and to identify the optimal intervention time of vagus nerve stimulation postconditioning to provide a maximal cardioprotection.
One hundred and forty anesthetized male Sprague Dawley rats (weighed290to320g) were randomly divided equally into seven groups (n=20in each group):sham group (S group), control group (C group), ischemic preconditioning group (IPC group), vagus nerve stimulation postconditioning at15min of myocardial ischemia period group (POESI15group), vagus nerve stimulation postconditioning immediately before myocardial reperfusion group (POESR0group), vagus nerve stimulation postconditioning at30min of myocardial reperfusion period group (POESR30group) and vagus nerve stimulation postconditioning at60min of myocardial reperfusion period group (POESR60group). After left thoracotomy in all rats, a6-0silk ligature was placed around the left anterior descending coronary artery (LAD) and encircled with a suture. In the groups other than S group, the LAD was ligated for30min followed by a120-min reperfusion. In C group, no additional intervention was performed. In IPC group, rats underwent three consecutive5-min LAD occlusion followed by a5-min reperfusion, which was performed before a30-min LAD ligation. In POESI15, POESR0, POESR30and POESR60groups, the right cervical vagus nerve was stimulated electrically at15min of ischemia, the time immediately before reperfusion,30min of reperfusion and60min of reperfusion and lasted for30min respectively. Throughout the experiment, the heart rate (HR), mean arterial pressure (MAP), and a lead II electrocardiogram were continuously monitored. The rectal temperature was maintained at36.5-37.5℃. Then, rats in each group were randomly divided equally into subgroup A and subgroup B. In subgroup A, blood samples were taken at30min,60min and120min of reperfusion for measuring serum concentrations of troponin I (TnI), myocardial-bound creatine kinase (CK-MB), tumor necrosis factor-a (TNF-a), high mobility group box1protein (HMGB1), intercellular adhesion molecule1(ICAM1), interleukin-1(IL-1), interleukin-6(IL-6) and interleukin-10(IL-10) by the kits specifically for rat. At the end of experiment, the infarct size (IS%) was assessed from excised hearts by Evans blue and triphenyltetrazolium chloride (TTC) staining. In subgroup B, the myocardial contents of TNF-a, HMGB1, ICAM1, IL-1, IL-6and IL-10were measured at the end of the experiment.
The results showed that rat's body weight, body temperature and baselines of HR, MAP and rate-pressure product (RPP) did not differ among the seven groups (P>0.05).
During the periods of ischemia and reperfusion, the HR was significantly lower in POESI15group than in S, C or IPC group. And during the period of reperfusion, the HR was significantly lower in POESR0, POESR30and POESR60groups than in S, C or IPC group. Compared to S group, the MAP and RPP were significantly decreased in C, IPC, POESI15, POESR0, POESR30and POESR60goups during the periods of both ischemia an reperfusion. Compared to IPC group, the number of rats suffering ischemic arrhythmia and arrhythmia score were significantly increased in C, POESI15, POESR0, POESR30and POESR60groups. Comparing to C group, the number of rats suffering reperfusion ventricular arrhythmia and arrhythmia score were significantly decreased in IPC, POESI15and POESR0groups.
The IS%and serum concentrations of cTnI and CK-MB were significantly higher in C group than in IPC, POESI15, POESR0, POESR30and POESR60groups. Compared to IPC group, the IS%was significantly increased in POESI15, POESR0, POESR30and PORSR60groups. Compared to POESI15group, the IS%, serum concentrations of cTnI and CK-MB were significantly increased in POESR60group. Compared to POESR0group, the IS%, serum concentrations of cTnI and CK-MB were increased significantly in POESR60group, but there was no difference in the IS%, secrum concentrations of cTnI and CK-MB between POESR0and POESR30goups. And there was no difference in the IS%and serum concentration of CK-MB between POESR30and POESR60groups.
Compared to S group, the serum concentration of TNF-a at30min,60min and120 min of reperfusion in C group, the serum concentration of HMGB1at60min of reperfusion in C, IPC and POESI15groups, the serum concentration of HMGB1at120min of reperfusion in C, POESR0, POESR30and POESR60groups, the serum concentration of ICAM1at120min of reperfusion in C, POESI15, POESRO, POESR30and POESR60groups, the serum concentration of IL-1at120min of reperfusion in C, IPC, POESRO, POESR30and POESR60groups, the serum concentration of IL-6at120min of reperfusion in C, IPC, POESR30, POESR60groups, the serum concentration of IL-10at120min of reperfusion in POESI15group were all significantly increased. Compared to C group, the serum concentration of TNF-α at30min and60min of reperfusion in both IPC and POESI15groups, the serum concentrations of TNF-α, HMGB1, ICAM1, IL-1and IL-6at120min of reperfusion in IPC, POESI15, POESR0, POESR30and POESR60groups were all significantly decreased. Compared to IPC group, the serum concentration of TNF-α at60min of reperfusion in POESI15group, the serum concentration of TNF-α at120min of reperfusion in POESR60group, the serum concentrations of HMGB1and ICAM1at120min of reperfusion in POESR0, POESR30and POESR60groups were all significantly increased. However, the serum concentration of IL-1at120min of reperfusion in POESI15group, the serum concentration of IL-6at120min of reperfusion in both POESI15and POESR0groups were all significantly decreased. Compared to POESI15group, the serum concentrations of HMGB1and ICAM1at120min of reperfusion in POESR0, POESR30and POESR60groups, the serum concentrations of IL-1, IL-6and TNF-α at120min of reperfusion in POESR60group were all significantly increased. Compared to POESR0group, the serum concentrations of HMGB1, IL-6and TNF-α at120min of reperfusin in POESR60group, the serum concentration of ICAM1at120min of reperfusion in both POESR30and POESR60groups were all significantly increased. The serum concentrations of TNF-α, HMGB1and ICAM1at120min of reperfusion were significantly increased in POESR60group than in POESR30group.
Compared to S group, the ischemic myocardial contents of TNF-α and HMGB1in C group, the non-ischemic myocardial content of TNF-α in both C and POESR60groups, the non-ischemic myocardial content of HMGB1in C group, the ischemic myocardial contents of ICAM1, IL-1and IL-6in C, POESI15, POESR0, POESR30and POESR60groups, the non-ischemic myocardial contents of ICAM1and IL-6in C and POESR60groups, the non-ischemic myocardial content of IL-1and both ischemic and non-ischemic myocardial contents of IL-10in C, IPC, POESI15, POESR0, POESR30 and POESR60groups were all significantly increased. However, the ischemic myocardial content of TNF-a in IPC group, the non-ischemic myocardial content of HMGB1in IPC, POESI15, POESRO and POESR30groups, the non-ischemic myocardial content of ICAM1in IPC, POESI15and POESRO groups, the non-ischemic myocardial content of IL-6in both IPC and POESI15groups were all significantly decreased comparing to S group. Compared to C group, both ischemic and non-ischemic myocardial contents of TNF-a, HMGB1, IL-1and IL-6in IPC, POESI15, POESRO, POESR30and POESR60groups were all significantly decreased, but both ischemic and non-ischemic myocardial contents of IL-10in POESI15group were significantly increased. Compared to IPC group, the ischemic myocardial content of TNF-a in POESI15, POESRO, POESR30and POESR60groups, the non-ischemic myocardial content of HMGB1in POESR60group, the ischemic myocardial content of ICAM1in POESI15, POESRO, POESR30and POESR60groups, the non-ischemic myocardial content of ICAM1and the ischemic myocardial content of IL-6in both POESR30and POESR60groups, the ischemic and non-ischemic myocardial contents of IL-1, the non-ischemic myocardial content of IL-6in POESRO, POESR30and POESR60groups were all significantly increased, but the non-ischemic myocardial content of HMGB1in POESI15group was significantly decreased. Compared to POESI15group, both ischemic and non-ischemic myocardial contents of TNF-a, the non-ischemic myocardial content of ICAM1, ischemic myocardial content of IL-1in both POESR30and POESR60groups, the ischemic myocardial contents of HMGB1and IL-6in POESR60group, the ischemic myocardial content of ICAM1, the non-ischemic myocardial contents of HMGB1, IL-1and IL-6in POESRO, POESR30and POESR60groups were significantly increased, but both ischemic and non-ischemic myocardial contents of IL-10in POESR60group were significantly decreased. Compared to POESRO group, the ischemic myocardial contents of TNF-a, HMGB1, IL-1and IL-6in POESR60group, the non-ischemic myocardial contents of HMGB1, IL-1and IL-6in POESR60group, the ischemic and non-ischemic myocardial contents of ICAMl in both POESR30and POESR60groups were all significantly increased. The ischemic and non-ischemic myocardial contents of ICAM1, IL-6and non-ischemic myocardial content of HMGB1were all significantly higher in POESR60group than in POESR30group.
Part2Experimental study on the protective effect of combined vagus nerve stimulation postconditioning and limb remote ischemic postconditioning against myocardial ischemia reperfusion injury in rats in vivo
Based on the results from the first part of the experiment, we designed this part to oberve whether combine vagus nerve stimulation postconditioning and limb remote ischemic postconditioning would gain an augmented cardioprotective effect.
One hundred and twenty anesthetized male SD rats (weighed290to320g) were randomly allocated into the six groups (n=20in each group):S group, C group, IPC group, POES group, limb remote ischemic postconditioning (LRIPOC) group and combined vagus nerve stimulation postconditioning and limb remote ischemic postconditioning (POES-LRIPOC) group. The procedures of C, IPC and POES groups were as same as those in the first part experiment, and the vagus nerve was stimulated at15min of myocardial ischemia at this part of experiment. In LRIPOC group, the bilateral hind legs were ligatured with an elastic tourniquet at20min of myocardial ischemia. In POES-LRIPOC group, rats received not only the same POES protocol as that of the POES group, but also the same LRIPOC protocol as that of the LRIPOC group. Then, rats in each group were futher randomly allocated into two subgroups. All testing variables in this part were as same as those in the first part of the experiment.
The results showed that rat's body weight, body temperature and baselines of HR, MAP and RPP did not differ among the six groups (P>0.05).
During the periods of ischemia and reperfusion, HR was significantly lower in POES and POES-LRIPOC groups than in S, C or IPC group. During the periods of ischemia and reperfusion, MAP and RPP were significantly lower in C, IPC, POES, LRIPOC and POES-LRIPOC groups than in S group. During the period of ischemia, the number of rats suffering ventricular arrhythmia and the score of arrhythmia were significantly increased in C, POES, LRIPOC and POES-LRIPOC groups comparing to IPC group. During the period of reperfusion, the number of rats suffering ventricular arrhythmia and the score of arrhythmia were significantly reduced in IPC, POES, LRIPOC and POES-LRIPOC groups comparing to C group. And during the period of reperfusion, the number of rats suffering ventricular arrhythmia and the score of arrhythmia were significantly reduced in IPC, POES and POES-LRIPOC groups comparing to LRIPOC group.
Compared to C group, the IS%, serum concentrations of cTnI and CK-MB were significantly decreased in IPC, POES, LRIPOC and POES-LRIPOC groups. Compared to IPC or POES-LRIPOC group, the IS%in POES and LRIPOC groups was significantly increased. Compared to POES group, the IS%and serum concentration of cTnI in LRIPOC group were significantly increased, but the serum concentration of CK-MB was significantly decreased in LRIPOC group. The serum concentrations of cTnI and CK-MB were significantly decreased in IPC and POES-LRIPOC groups than in LRIPOC group.
Compared to S group, the serum concentration of TNF-a at30min of reperfusion in C and LRIPOC groups, the serum concentration of TNF-a at60min and120min of reperfusion in C group, the serum concentration of HMGB1at60min of reperfusion in C, IPC, POES, LRIPOC and POES-LRIPOC groups, the serum concentration of HMGB1at120min of reperfusion in C and LRIPOC groups, the serum concentration of ICAM1at120min of reperfusion in C, POES and LRIPOC groups, the serum concentrations of IL-1and IL-6at120min of reperfusion at C, IPC and LRIPOC groups, the serum concentration of IL-10at120min of reperfusion in POES and POES-LRIPOC groups were all significantly increased, but the serum concentration of TNF-a at60min of reperfusion in IPC and POES-LRIPOC groups, the serum concentration of TNF-a at120min of reperfusion in IPC, POES, LRIPOC and POES-LRIPOC groups were all significantly decreased. Compared to C group, the serum concentration of TNF-a at30min,60min,120min of reperfusion and the serum concentrations of HMGB1, ICAM1, IL-1, IL-6at120min of reperfusion in IPC, POES, LRIPOC and POES-LRIPOC groups, the serum concentration of HMGB1at60min of reperfusion in IPC group were all significantly decreased, but the serum concentration of IL-10at120min of reperfusion in POES-LRIPOC group was significantly increased. Compared to IPC group, the serum concentration of TNF-a at60min of reperfusion in POES and LRIPOC groups, the serum concentrations of HMGB1and ICAM1at120min of reperfusion in LRIPOC group were all significantly increased, but the serum concentrations of IL-1and IL-6in POES and POES-LRIPOC groups were all significantly decreased. Compared to POES group, the serum concentration of TNF-a at60min of reperfusion, the serum concentrations of HMGB1, ICAM1, IL-1and IL-6at120min of reperfusion in LRIPOC group were all significantly increased, but the serum concentration of ICAM1in POES-LRIPOC group was significantly decreased. The serum concentrations of TNF-a at30min,60min and120min of reperfusion, the serum concentrations of HMGB1, ICAM1, IL-1and IL-6at120min of reperfusion were significantly decreased in POES-LRIPOC group than in LRIPOC group.
Compared to S group, the ischemic myocardial contents of TNF-a and HMGB1, the non-ischemic myocardial contents of TNF-a, HMGB1and ICAM1in C group, the ischemic myocardial content of ICAM1in C, POES, LRIPOC and POES-LRIPOC groups, the ischemic myocardial contents of IL-1and IL-6in C, POES and LRIPOC groups, the ischemic myocardial content of IL-10, the non-ischemic myocardial contents of IL-1and IL-10in C, IPC, POES, LRIPOC and POES-LRIPOC groups, the non-ischemic myocardial content of IL-6in C and LRIPOC groups were all significantly increased, but the ischemic myocardial content of TNF-a in IPC and POES-LRIPOC groups, the non-ischemic myocardial content of HMGB1in IPC, POES, LRIPOC and POES-LRIPOC groups, the non-ischemic myocardial contents of ICAM1and IL-6in IPC, POES and POES-LRIPOC groups were all significantly decreased. Compared to C group, the ischemic and non-ischemic myocardial contents of TNF-a, HMGB1, ICAM1, IL-1and IL-6in IPC, POES, LRIPOC and POES-LRIPOC groups were all significantly decreased, but the ischemic and non-ischemic myocardial contents of IL-10in POES and POES-LRIPOC groups were significantly increased. Compared to IPC group, the ischemic myocardial contents of TNF-a, ICAM1and IL-1in POES and LRIPOC groups, the ischemic and non-ischemic myocardial contents of IL-10in POES-LRIPOC group, the ischemic myocardial content of IL-6and the non-ischemic myocardial contents of ICAM1, IL-1and IL-6in LRIPOC group were all significantly increased, but the ischemic myocardial content of HMGB1in POES-LRIPOC group, the non-ischemic myocardial content of HMGB1in POES and POES-LRIPOC groups were all significantly decreased. Compared to POES group, the ischemic myocardial contents of TNF-a, ICAM1and IL-1in POES-LRIPOC group, the ischemic myocardial content of IL-10in LRIPOC group were all significantly decreased, but the non-ischemic myocardial content of IL-10in POES-LRIPOC group, the non-ischemic myocardial contents of HMGB1, ICAM1, IL-1and IL-6, ischemic myocardial contents of ICAM1, IL-1and IL-6in LRIPOC group were all significantly increased. Compared to LRIPOC group, the ischemic myocardial contents of TNF-a, ICAM1, IL-1and IL-6, the non-ischemic myocardial contents of HMGB1, ICAM1, IL-1and IL-6in POES-LRIPOC group were all significantly decreased, but the ischemic and non-ischemic myocardial contents of IL-10were significantly increased.
Part3Roles of the PI3K/Akt and JAK/STAT signal pathways in the cardioprotections of vagus nerve stimulation postconditioning and combined vagus nerve stimulation postconditioning and limb remote ischemic postconditioning
The aims of this part of the experiment were to explore the modulating roles of PI3K/Akt and JAK/STAT signal pathways in cardioprotective effects of vagus nerve stimulation postconditioning and combined vagus nerve stimulation postconditioning and limb remote ischemic postconditioning.
Twenty anesthetized male SD rats (weighed290to320g) were randomly equally divided into four groups (n=5in each group):control group, POES group, LRIPOC group and combined POES and LRIPOC group. After60min of reperfusion, the myocardial tissues from the area at risk in the left ventricle and non-ischemic area in the right ventricule were harvested from excised hearts. Total RNA and total protein were extracted from all myocardial samples, respectively. The real time quantitative polymerase chain reaction (RQ-PCR) was used to quantify the mRNA expression of Akt and STAT3genes in all groups. Also, phosphorylated Akt and phosphorylated STAT3in all samples were assessed by Western-blotting technique.
Compared to C group, ischemic and non-ischemic myocardial phosphorylated Akt (p-Akt) and phosphorylated STAT3(p-STAT3) were all significantly increased in POES, LRIPOC and POES-LRIPOC groups. The ischemic and non-ischemic myocardial p-Akt and p-STAT3were significantly increased in POES-LRIPOC group than in POES or LRIPOC group.
The results of RQ-PCR demonstrated that the mRNA expression of ischemic and non-ischemic myocardial Akt and STAT3genes were significantly enhanced in POES-LRIPOC group compared to C group. Also, the mRNA expression of Akt and STAT3genes were significantly higher in POES-LRIPOC group than in POES or LRIPOC group.
Conclusion
Based on the results of all experiments, the following conclusions can be drawn:
1. Vagus nerve stimulation postconditioning performed at15min of myocardial ischemia, the time immediately before myocardial reperfusion,30min of myocardial reperfusion and60min of myocardial reperfusion can all significantly reduce the infarct size, decrease serum concentrations of cTnI and CK-MB during myocardial ischemia reperfusion injury. Moreover, the cardioprotection provided by vagus nerve stimulation postconditioning at60min of myocardial reperfusion is weakest, while the cardioprotection provided by vagus nerve stimulation postconditioning at15min of myocardial ischemia is strongest but still weaker than ischemic preconditioning.
2. Ischemic preconditioning and vagus nerve stimulation postconditioning performed at different time points can all significantly reduce the ventricular arrhythmias during myocardial reperfusion period. Among vagus nerve stimulation postconditionings performed at different time points, vagus nerve stimulation postconditioning at15min of myocardial ischemia can provide the strongest anti-arrhythmic effect.
3. Combined vagus nerve stimulation postconditioning and limb remote ischemic postconditioning can provide a stronger cardioprotection which is comparable to ischemic preconditioning.
4. Ischemc preconditioning, vagus nerve stimulation postconditioning performed at different time points, limb remote ischemic postconditioning and combined vagus nerve stimulation postconditioning and limb remote ischemic postconditioning can all provide cardioprotections by inhibiting inflammation during myocardial ischemia reperfusion injury.
5. Protein phosphorylation upregulation of related genes involved in both PI3K/Akt and JAK/STAT signal pathways mediates the cardioprotections of vagus nerve stimulation postconditioning and limb remote ischemic postconditoning. And the mRNA expression upregulation of related genes involved in both PI3K/Akt and JAK/STAT signal pathways mediates the cardioprotection of combined vagus nerve stimulation postconditioning and limb remote ischemic postconditioning. Also, the protein phosphorylation upregulation of related genes involved in both PI3K/Akt and JAK/STAT signal pathways probably contributes to the cardioprotection of combined vagus nerve stimulation postconditioning and limb remote ischemic postconditioning
研究表明,在急性心肌缺血恢复血流灌注后,由缺血-再灌注损伤(ischemia reperfusion injury, IRI)所致的心肌梗死后死亡率仍然高达10%。动物实验亦发现,心肌缺血时高达50%的最终心肌梗死面积是归因于IRI。目前,已经公认缺血预处理是最为强大的内源性心肌保护干预措施。然而,由于心肌缺血事件的不可预测性,所以在临床实践中很难对其采取预先干预措施。因此,除了能够在实施心脏手术的患者选择性应用之外,缺血预处理的临床应用价值十分有限。缺血后处理则解决了临床干预时机选择的问题,而且其也已被证明具有确切的心肌保护作用。但是,诸如反复阻塞冠状动脉这样的操作有导致病变冠状动脉破裂或粥样斑块脱落等并发症的高度风险,故其临床应用价值也十分有限。相比之下,肢体远隔缺血后处理则能够避免在心脏直接进行操作,而且大量研究表明其对心肌IRI具有明确的保护作用。此外,肢体远隔缺血后处理还具有安全、实施简单和费用低廉等优点。因此,肢体远隔缺血后处理不失为临床治疗心肌IRI的一种较佳选择。
现已明确,炎症反应在心肌IRI的发生和发展过程中发挥着极为重要的致病作用,并且调节炎症反应可以减轻心肌IRI。晚近研究发现,迷走神经同样具有免疫炎症调节功能,其激活后能够通过胆碱能抗炎通路(cholinergic anti-inflammatory pathway)而实现对炎症反应的调控。在内毒素血症、结肠炎、风湿性关节炎和IRI等炎症性疾病时,迷走神经刺激能够通过抑制炎症细胞募集和炎症细胞因子释放而调控炎症反应,进而发挥其保护作用。虽然已经证实迷走神经刺激能够减小IRI所致的心肌梗死面积,但是目前尚无研究系统观察迷走神经刺激后处理对心肌缺血-再灌注损伤时心肌局部与全身炎症反应的影响。
联合应用不同的干预措施以获得有益的强效心肌保护效果一直是心肌IRI保护研究领域的重要方向,而且迷走神经刺激后处理和肢体远隔缺血后处理是两种作用机制明显不同的心肌保护干预措施。因此,我们设计了这个随机对照实验,主要目的包括：①观察迷走神经刺激后处理对心肌IRI保护的有效性、可用性和最佳干预时间；②评价将迷走神经刺激后处理和肢体远隔缺血后处理这两种极具临床应用前景的简单干预措施联合应用能否获得有益的协同性心肌保护作用；③观察PI3K/Akt和JAK/STAT信号转导通路在迷走神经刺激后处理、肢体远隔缺血后处理、联合应用迷走神经刺激后处理和肢体远隔缺血后处理心肌保护作用中的地位,以探索不同心肌保护干预措施的内在作用机制。本实验分为三个部分：
第1部分：迷走神经刺激后处理对心肌缺血-再灌注损伤的保护作用及其最佳干预时间的研究
第1部分实验的目的是采用大鼠在体心肌IRI模型比较性观察在不同时间点应用迷走神经刺激后处理对心肌IRI及其炎症反应的影响,以确定迷走神经刺激后处理的心肌保护作用及其最佳干预时间。
将140只体重290～320g的成年雄性Sprague Dawley (SD)大鼠麻醉后随机平均分为七组(每组20只)：空白对照组(S组)；对照组(C组)；缺血预处理组(IPC组)；心肌缺血15min迷走神经刺激后处理组(POESI15组)；再灌注前迷走神经刺激后处理组(POESRO组)；再灌注30min迷走神经刺激后处理组处理组(POESR30组)；再灌注60min迷走神经刺激后处理组(POESR60组)。所有大鼠开胸后采用丝线将其冠状动脉左前降支(left anterior descending coronary artery, LAD)套扎做成活结。除S组之外,所用大鼠均接受局部心肌缺血30min(阻断LAD)和再灌注120min(开放LAD)的处理。C组不采用任何其他干预措施；IPC组在结扎LAD前进行3个循环的缺血预处理,每个循环是由5min的LAD阻断和5min的LAD开放组成,总处理时间是30min; POESI15、POESR0、POESR30和POESR60组是分别在心肌缺血15min时、心肌再灌注前即刻、心肌再灌注30min时和心肌再灌注60min时对大鼠的右侧迷走神经进行电刺激,持续时间为30min。实验过程中,连续监测心率(heart rate, HR)、平均动脉压(mean arterial pressure, MAP)和Ⅱ导联心电图(electrocardiogram, ECG),并保持大鼠直肠温度在36.5～37.5℃之间。然后,将每组大鼠进一步随机平均分为2个亚组(每亚组10只),第1亚组在再灌注30min、60min和120min时抽取血液标本,采用大鼠专用试剂盒分别测定血清心肌肌钙蛋白I (cardiac troponin-I, cTnI)、肌酸激酶心肌型同工酶(myocardial-bound creatine kinase, CK-MB)、肿瘤坏死因子-α(tumor necrosis factor-α, TNF-α)、高迁移率组蛋白1(high mobility group box1protein, HMGB1)、细胞间粘附分子1(intercellular adhesion molecule1, ICAM1)、白介素-1(interleukin-1, IL-1)、白介素-6(interleukin-6, IL-6)和白介素-10(interleukin-10, IL-10)的浓度；在实验结束时,采用伊文思蓝和氯化三苯基四氮唑双重染色技术检测心肌梗死面积(infarct size, IS%)。在实验结束时,第2亚组用于检测缺血区心肌组织和非缺血区心肌组织TNF-α、HMGB1、ICAM1、IL-1、IL-6和IL-10的含量。
结果显示,各组大鼠的一般情况和心肌缺血前血流动力学参数的基础值比较差异无显著统计学意义。
与S组、C组或IPC组相比,POESI15组的HR在缺血期和再灌注期间均明显降低,POESRO组、POESR30组和POESR60组的HR在再灌注期间明显降低。与S组相比,C组、IPC组、POESI15组、POESRO组、POESR30组和POESR60组在缺血期和再灌注期的MAP和心率血压乘积(rate-pressure product, RPP)均明显降低。与IPC组相比,C组、POESI15组、POESRO组、POESR30组和POESR60组缺血期发生室性心律失常的大鼠数目明显增多,而且缺血期室性心律失常评分亦明显增高。与C组相比,IPC组、POESI15组和POESRO组再灌注初期发生室性心动过速(ventricular tachycardia, VT)的大鼠数目明显减少,而且再灌注初期室性心律失常评分亦明显降低。
与C组相比,IPC组、POESI15组、POESRO组、POESR30组和POESR60组的IS%值、血清cTnI和CK-MB浓度均明显降低；与IPC组相比,POESI15组、POESRO组.POESR30组和POESR60组的IS%值均明显增高；与POESI15组相比,POESR60组的IS%值、血清cTnI、CK-MB浓度明显增高,POESRO组和POESR30组的IS%值、血清cTnI和CK-MB浓度无显著统计学差异；与POESRO组相比,POESR60组的IS%值、血清cTnI和CK-MB浓度明显增高,POESR30组的IS%值、血清cTnI和CK-MB浓度无显著统计学差异；与POESR30组相比,POESR60组的IS%值、血清CK-MB浓度无显著统计学差异。
与S组相比,C组再灌注30min、60min和120min时血清TNF-a浓度明显增高；C组、IPC组和POESI15组再灌注60min时血清HMGB1浓度,C组、POESRO组、POESR30组和POESR60组再灌注120min时血清HMGB1浓度明显增高；C组、POESI15组、POESRO组、POESR30组和POESR60组再灌注120min时血清ICAM1浓度明显增高；C组、IPC组、POESRO组、POESR30组和POESR60组再灌注120min时血清IL-1的浓度明显增高；C组、IPC组、POESR30组和POESR60组再灌注120mmin时血清IL-6浓度明显增高；POESI15组再灌注120min时血清IL-10浓度明显增高。与C组相比,IPC组和POESI15组再灌注30min和60min时血清TNF-a浓度明显降低；IPC组、POESI15组、POESRO组、POESR30组和POESR60组再灌注120min时血清TNF-α、HMGB1、ICAM1、IL-1、IL-6浓度明显降低。与IPC组相比,POESI15组再灌注60mmin时血清TNF-a浓度明显增高；POESR60组再灌注120min时血清TNF-a浓度明显增高；POESRO组、POESR30组和POESR60组再灌注120min时血清HMGB1和ICAM1浓度明显增高;POESI15组再灌注120mmin时血清IL-1的浓度明显降低；POESI15组和POESRO组再灌注120min时血清IL-6浓度明显降低。与POESI15组相比,POESRO组、POESR30组和POESR60组再灌注120min时血清HMGB1和ICAM1的浓度明显增高；POESR60组再灌注120min时血清IL-1、IL-6和TNF-a的浓度明显增高。与POESRO组相比,POESR60组再灌注120min时血清HMGB1、IL-6和TNF-a的浓度明显增同；POESR30组和POESR60组再灌注120min时血清ICAM1浓度明显增高。与POESR30组相比,POESR60组再灌注120min时血清HMGB1、ICAM1和TNF-α浓度明显增高。
与S组相比,C组缺血区心肌组织TNF-α和HMGB1含量明显增高,IPC组缺血区心肌组织TNF-α含量明显降低；C组和POESR60组非缺血区心肌组织TNF-a含量明显增高；C组非缺血区心肌组织HMGB1含量明显增高,IPC组、POESI15组、POESRO组和POESR30组非缺血区心肌组织HMGB1含量明显降低；C组、POESI15组、POESRO组、POESR30组和POESR60组缺血区心肌组织ICAM1、IL-1和IL-6含量明显增高；C组和POESR60组非缺血区心肌组织ICAM1和IL-6含量明显增高,IPC组、POESI15组和POESRO组非缺血区心肌组织ICAM1含量明显降低；C组、IPC组、POESI15组、POESRO组、POESR30组和POESR60组非缺血区心肌组织IL-1含量、缺血区心肌组织和非缺血区心肌组织IL-10含量明显增高；IPC组和POESI15组非缺血区心肌组织IL-6含量明显降低。与C组相比,IPC组、POESI15组、POESRO组、POESR30组和POESR60组缺血区心肌组织和非缺血区心肌组织TNF-α、HMGB1、IL-1和IL-6含量明显降低；POESI15组缺血区心肌组织和非缺血区心肌组织IL-10含量明显增高。与IPC组相比,POESI15组、POESRO组、POESR30组和POESR60组缺血区心肌组织TNF-a含量明显增高；POESI15组非缺血区心肌组织HMGB1含量明显降低,POESR60组非缺血区心肌组织HMGB1含量明显增高；POESI15组、POESRO组、POESR30组和POESR60组缺血区心肌组织ICAM1含量明显增高；POESR30组和POESR60组非缺血区心肌组织ICAM1、缺血区IL-6含量明显增高；POESRO组、POESR30组和POESR60组缺血区心肌组织和非缺血区心肌组织IL-1、非缺血区心肌组织IL-6含量明显增高。与POESI15组相比,POESR30组和POESR60组缺血区心肌组织和非缺血区心肌组织TNF-a含量、非缺血区心肌组织ICAM1含量、缺血区心肌组织IL-1含量明显增高；POESR60组缺血区心肌组织HMGB1、IL-6含量明显增高,缺血区心肌组织和非缺血区心肌组织IL-10含量明显降低；POESRO组、POESR30组和POESR60组缺血区心肌组织ICAM1含量、非缺血区心肌组织HMGB1、IL-1和IL-6含量明显增高。与POESRO组相比,POESR60组缺血区心肌组织TNF-α、HMGB1、IL-1、IL-6含量、非缺血区心肌组织HMGB1、IL-1和IL-6含量明显增高；POESR30组和POESR60组缺血区心肌组织和非缺血区心肌组织ICAM1含量明显增高。与POESR30组相比,POESR60组缺血区心肌组织和非缺血区心肌组织ICAM1和IL-6含量以及非缺血区心肌组织HMGB1含量均明显增高。
第2部分：联合应用迷走神经刺激后处理和肢体远隔缺血后处理对心肌缺血-再灌注损伤保护作用的研究
根据第1部分实验的结果,在确定迷走神经刺激后处理最佳干预时间的基础上我们设计了这部分实验,其目的是评价联合应用迷走神经刺激后处理和肢体远隔缺血后处理能否获得增强的心肌保护作用。
将120只体重290-320g的成年雄性SD大鼠麻醉后随机平均分为六组(每组20只)：空白对照组(S组)；对照组(C组)；缺血预处理组(IPC组)；迷走神经刺激后处理组(POES组)；肢体远隔缺血后处理组(LRIPOC组)；联合应用迷走神经刺激后处理和肢体远隔缺血后处理组(POES-LRIPOC组)。C组和IPC组的处理同第1部分实验；POES组是根据第1部分实验获得的结果在最佳时间点进行迷走神经刺激；LRIPOC组的基本处理与C组相同,在心肌缺血20min时采用止血带结扎大鼠双侧后肢造成双后肢缺血10mmin,并在开放LAD实施心肌血流再灌注的同时开放后肢血流灌注；POES-LRIPOC组的基本处理与C组相同,迷走神经刺激后处理的实施方法同POES组,肢体远隔缺血后处理的实施方法同LRIPOC组。然后,将每组大鼠进一步随机平均分为2个亚组(每亚组10只),各组检测项目与第1部分实验相同。
结果显示,各组大鼠的一般情况和心肌缺血前血流动力学参数的基础值比较差异无显著统计学意义。
与S组、C组或IPC组相比,POES组和POES-LRIPOC组的HR在缺血期和再灌注期明显降低。与S组相比,C组、IPC组、POES组、LRIPOC组和POES-LRIPOC组的MAP和RPP在缺血期和再灌注期均明显降低。与IPC组相比,C组、POES组、LRIPOC组和POES-LRIPOC组缺血期室性心律失常发生率和室性心律失常评分明显增高。与C组相比,IPC组、POES组、LRIPOC组和POES-LRIPOC组再灌注期室性心律失常发生率和室性心律失常评分均明显降低；与LRIPOC组相比,IPC组、POES组和POES-LRIPOC组再灌注期间室性心律失常发生率和室性心律失常评分明显降低。
与C组相比,IPC组、POES组、LRIPOC组和POES-LRIPOC组的IS%值、血清cTnI和CK-MB浓度均明显降低；与IPC组或POES-LRIPOC组相比,POES组和LRIPOC组的IS%值明显增高；与POES组相比,LRIPOC组的IS%值和血清cTnl浓度明显增高,LRIPOC组的血清CK-MB浓度明显降低。与LRIPOC组相比,IPC组和POES-LRIPOC组的血清cTnI和CK-MB浓度均明显降低。
与S组相比,C组和LRIPOC组再灌注30min时血清TNF-a浓度明显增高；C组再灌注60min和120min时血清TNF-a浓度明显增高,IPC组和POES-LRIPOC组再灌注60min时血清TNF-a浓度明显降低；IPC组、POES组、LRIPOC组和POES-LRIPOC组再灌注120min时血清TNF-a浓度明显降低；C组、IPC组、POES组、LRIPOC组和POES-LRIPOC组再灌注60min时血清HMGB1浓度明显增高；C组和LRIPOC组再灌注120min时血清HMGB1浓度明显增高；C组、POES组和LRIPOC组再灌注120min时血清ICAM1浓度明显增高；C组、IPC组和LRIPOC组再灌注120min时血清IL-1和IL-6浓度明显增高；POES组和POES-LRIPOC组再灌注120min时血清IL-10浓度明显增高。与C组相比,IPC组、POES组、LRIPOC组和POES-LRIPOC组再灌注30min、60min和120min时血清TNF-a浓度、再灌注120min时血清HMGB1、ICAM1、IL-1、IL-6浓度明显降低；IPC组再灌注60min时血清HMGB1浓度明显降低；POES-LRIPOC组再灌注120min时血清IL-10浓度明显增高。与IPC组相比,POES组和LRIPOC组再灌注60min时血清TNF-a浓度明显增高；LRIPOC组再灌注120min时血清HMGB1和ICAM1浓度明显增高；POES组和POES-LRIPOC组再灌注120min时血清IL-1和IL-6浓度明显降低。与POES组相比,LRIPOC组再灌注60min时血清TNF-a浓度、再灌注120min时血清HMGB1、ICAM1、IL-1和IL-6浓度明显增高；POES-LRIPOC组再灌注120min时血清ICAM1浓度明显降低。与LRIPOC组相比,POES-LRIPOC组再灌注30min、60min和120min时血清TNF-a浓度、再灌注120min时血清HMGB1、ICAM1、IL-1和IL-6浓度均明显降低。
与S组相比,C组缺血区心肌组织TNF-a和HMGB1含量以及非缺血区心肌组织TNF-α、HMGB1和ICAM1含量明显增高；IPC组和POES-LRIPOC组缺血区心肌组织TNF-a含量明显降低；IPC组、POES组、LRIPOC组和POES-LRIPOC组非缺血区心肌组织HMGB1含量明显降低；C组、POES组、LRIPOC组和POES-LRIPOC组缺血区心肌组织ICAM1含量明显增高；IPC组、POES组和POES-LRIPOC组非缺血区心肌组织ICAM1和IL-6含量明显降低；C组、POES组和LRIPOC组缺血区心肌组织IL-1和IL-6含量明显增高；C组、IPC组、POES组、LRIPOC组和POES-LRIPOC组非缺血区心肌组织IL-1、IL-10含量、缺血区心肌组织IL-10含量明显增高；C组和LRIPOC组非缺血区心肌组织IL-6含量明显增高。与C组相比,IPC组、POES组、LRIPOC组和POES-LRIPOC组缺血区心肌组织和非缺血区心肌组织TNF-α、HMGB1、ICAM1、IL-1和IL-6含量均明显降低；POES组和POES-LRIPOC组缺血区心肌组织和非缺血区心肌组织IL-10含量明显增高。与IPC组相比,POES组和LRIPOC组缺血区心肌组织TNF-α、ICAM1和IL-1含量明显增高；POES-LRIPOC组缺血区心肌组织HMGB1含量明显降低,缺血区心肌组织和非缺血区心肌组织IL-10含量明显增高；POES组和POES-LRIPOC组非缺血区心肌组织HMGB1含量明显降低；LRIPOC组非缺血区心肌组织ICAM1、IL-1和IL-6含量,缺血区心肌组织IL-6含量明显增高。与POES组相比,POES-LRIPOC组缺血区心肌组织TNF-α、ICAM1和IL-1含量明显降低,非缺血区心肌组织IL-10含量明显增高；LRIPOC组非缺血区心肌组织HMGB1、ICAM1、IL-1和IL-6含量以及缺血区心肌组织ICAM1、IL-1和IL-6含量明显增高,缺血区心肌组织IL-10含量明显降低。与LRIPOC组相比,POES-LRIPOC组缺血区心肌组织TNF-α、ICAM1、IL-1和IL-6含量以及非缺血区心肌组织HMGB1、ICAM1、IL-1和IL-6含量明显降低,缺血区心肌组织和非缺血区心肌组织IL-10含量明显增高。
第3部分:PI3K/Akt和JAK/STAT信号转导通路在迷走神经刺激后处理以及联合应用迷走神经刺激后处理和肢体远隔缺血后处理心肌保护作用机制中地位的研究
本部分实验的目的是探讨PI3K/Akt和JAK/STAT信号转导通路在单独应用迷走神经刺激后处理以及联合应用迷走神经刺激后处理和肢体远隔缺血后处理心肌保护作用机制中的地位。
将20只体重290-320g的成年雄性SD大鼠麻醉后随机平均分为四组(每组5只)：对照组(C组)；迷走神经刺激后处理组(POES组)；肢体远隔缺血后处理组(LRIPOC组)；联合应用迷走神经刺激后处理和肢体远隔缺血后处理组(POES-LRIPOC组)。各组的处理基本同本实验第二部分,但是在开放LAD实施再灌注60min时结束实验,分别取大鼠左心室缺血区心肌标本和右心室非缺血区心肌标本。从缺血与非缺血区心肌标本中提取总蛋白和总RNA,采用实时定量聚合酶链反应(Real-time quantitative polymerase chain reaction, RQ-PCR)技术观察Akt和STAT3基因mRNA在缺血区心肌组织和非缺血区心肌组织的表达情况,并通过免疫蛋白印迹分析(Western-blotting)技术观察缺血区心肌组织和非缺血区心肌组织Akt和STAT3蛋白磷酸化的情况。
RQ-PCR结果显示,与C组相比,POES-LRIPOC组缺血区心肌组织和非缺血区心肌组织Akt基因和STAT3基因mRNA表达均明显增强；与POES组相比,POES-LRIPOC组缺血区心肌组织和非缺血区心肌组织Akt基因和STAT3基因mRNA表达明显增强；与LRIPOC组相比,POES-LRIPOC组缺血区心肌组织和非缺血区心肌组织Akt基因和STAT3基因mRNA表达明显增强。
Western-blotting结果显示,与C组相比,POES组、LRIPOC组和POES-LRIPOC组的缺血区心肌组织和非缺血区心肌组织p-Akt蛋白和p-STAT3蛋白的灰度值明显增加；与POES组相比,POES-LRIPOC组的缺血区心肌组织和非缺血区心肌组织p-Akt蛋白和p-STAT3蛋白的灰度值明显增加；与LRIPOC组相比,POES-LRIPOC组的缺血区心肌组织和非缺血区心肌组织p-Akt蛋白和p-STAT3蛋白的灰度值明显增加。
结论
通过本实验,我们得出以下结论：
1.心肌缺血15min时、再灌注前即刻、再灌注30mmin和再灌注60min时实施迷走神经刺激后处理均能够明显减小IRI所致的心肌梗死面积,并明显降低血清cTnI和CK-MB浓度,其中以在再灌注60min实施迷走神经刺激后处理的心肌保护效果最差,以在心肌缺血15mmin时实施迷走神经刺激后处理的心肌保护效果最强,但是迷走神经刺激后处理的心肌保护作用弱于缺血预处理。
2.缺血预处理、缺血期和再灌注期不同时间点进行迷走神经刺激后处理均能明显抑制再灌注期室性心律失常的发生；缺血15min时实施迷走神经刺激后处理抑制再灌注期心律失常的作用较其他时间点进行迷走神经刺激后处理更强。
3.联合应用迷走神经刺激后处理和肢体远隔缺血后处理能够获得更强的心肌保护作用,并且该心肌保护作用与缺血预处理的心肌保护作用几无差异。
4.缺血预处理、缺血期和再灌注期不同时间点进行迷走神经刺激后处理、肢体远隔缺血后处理、联合应用迷走神经刺激后处理和肢体远隔缺血后处理均能通过抑制心肌IRI过程中的炎症反应而发挥心肌保护作用。
5. PI3K/Akt和JAK/STAT信号转导通路相关基因在转录后蛋白磷酸化水平的上调参与了迷走神经刺激后处理和肢体远隔缺血后处理的心肌保护作用；而PI3K/Akt和JAK/STAT信号转导通路相关基因mRNA水平的上调则参与了联合应用迷走神经刺激后处理和肢体远隔缺血后处理的心肌保护。同时,联合应用迷走神经刺激后处理和肢体远隔缺血后处理的心肌保护作用机制可能还涉及了PI3K/Akt和JAK/STAT信号转导通路蛋白磷酸化水平的上调。
Background
Studies have shown that the mortality rate attributed to myocardial ischemia reperfusion injury (IRI) is still up to10%after prompt restoration of blood flow in the infarct-related coronary. In addition, many animal researches have shown that the IRI is responsible for up to50%of the final infarct size during acute myocardial ischemia. Although the ischemic preconditioning (IPC) remains the most powerful cardioprotective measure, its clinical application has been hampered by the requirement of intervention before onset of acute myocardial ischemia, which is clearly impossible in the setting of acute myocardial infarction. Ischemic postconditioning (IPOC) can be triggered during the clinically applicable period of myocardial reperfusion, which has already been shown cardioprotective. However, it can cause dangerous complications including rupture of diseased coronary artery and fall off of atheromatous plaque, which attribute to the requirement of repeated occlusion of coronary artery. Thus, the clinical application of IPOC is quite limited too. In contrast, limb remote ischemic postconditioning (LRIPOC) can be operated away from the heart and it has definitely cardioprotective effects. In addition, LRIPOC is easy to operate, safe and low-cost. As a result, LRIPOC is really a good choice to treat myocardial IRI.
Endogenous inflammatory response is a key factor in formation and progression of myocardial IRI. Recently, the immunoregulation of vagus nerve has been demonstrated, which can modulate inflammation by the cholinergic anti-inflammatory pathway when activated. During inflammatory diseases such as endotoxemia, colonitis, rheumatic arthritis and IRI, vagus nerve stimulation can provide protection by inhibiting inflammatory cells recruitment and inflammatory cytokines release. Moreover, it has been demonstrated that vagus nerve stimulation can reduce the infarct size caused by myocardial IRI. However, there has been no research observing the effects of vagus nerve stimulation postconditioning (POES) on local myocardial and systemic inflammation during myocardial IRI.
Combining different interventions to obtain an augmented cardioprotection is always one of the most popular research focuses in the area of myocardial IRI. Obviously, POES and LRIPOC might be triggered by different mechanisms. As a result, this randomized, controlled animal experimental study was designed and the aims of the present study were:1) to investigate the validity, usability and optimal intervention time of cardioprotection provided by vagus nerve stimulation postconditioning during myocardial IRI;2) to determine whether there was a synergistic cardioprotection by combination of POES and LRIPOC;3) to assess roles of both PI3K/Akt and JAK/STAT signal pathways in the cardioprotection of combined POES and LRIPOC, in order to explore the inherent mechanism of the interaction between POES and LEIPOC. This study was divided into three parts.
Part1Experimental study on cardioprotective and anti-inflammatory effects and optimal intervention time of vagus nerve stimulation postconditioning in rat with myocardial ischemia reperfusion injury in vivo
In this part of the experiment, an in vivo rat model of myocardial IRI was used to compare the cardioprotections and anti-inflammatory effects of vagus nerve stimulation postconditioning at different time points, and to identify the optimal intervention time of vagus nerve stimulation postconditioning to provide a maximal cardioprotection.
One hundred and forty anesthetized male Sprague Dawley rats (weighed290to320g) were randomly divided equally into seven groups (n=20in each group):sham group (S group), control group (C group), ischemic preconditioning group (IPC group), vagus nerve stimulation postconditioning at15min of myocardial ischemia period group (POESI15group), vagus nerve stimulation postconditioning immediately before myocardial reperfusion group (POESR0group), vagus nerve stimulation postconditioning at30min of myocardial reperfusion period group (POESR30group) and vagus nerve stimulation postconditioning at60min of myocardial reperfusion period group (POESR60group). After left thoracotomy in all rats, a6-0silk ligature was placed around the left anterior descending coronary artery (LAD) and encircled with a suture. In the groups other than S group, the LAD was ligated for30min followed by a120-min reperfusion. In C group, no additional intervention was performed. In IPC group, rats underwent three consecutive5-min LAD occlusion followed by a5-min reperfusion, which was performed before a30-min LAD ligation. In POESI15, POESR0, POESR30and POESR60groups, the right cervical vagus nerve was stimulated electrically at15min of ischemia, the time immediately before reperfusion,30min of reperfusion and60min of reperfusion and lasted for30min respectively. Throughout the experiment, the heart rate (HR), mean arterial pressure (MAP), and a lead II electrocardiogram were continuously monitored. The rectal temperature was maintained at36.5-37.5℃. Then, rats in each group were randomly divided equally into subgroup A and subgroup B. In subgroup A, blood samples were taken at30min,60min and120min of reperfusion for measuring serum concentrations of troponin I (TnI), myocardial-bound creatine kinase (CK-MB), tumor necrosis factor-a (TNF-a), high mobility group box1protein (HMGB1), intercellular adhesion molecule1(ICAM1), interleukin-1(IL-1), interleukin-6(IL-6) and interleukin-10(IL-10) by the kits specifically for rat. At the end of experiment, the infarct size (IS%) was assessed from excised hearts by Evans blue and triphenyltetrazolium chloride (TTC) staining. In subgroup B, the myocardial contents of TNF-a, HMGB1, ICAM1, IL-1, IL-6and IL-10were measured at the end of the experiment.
The results showed that rat's body weight, body temperature and baselines of HR, MAP and rate-pressure product (RPP) did not differ among the seven groups (P>0.05).
During the periods of ischemia and reperfusion, the HR was significantly lower in POESI15group than in S, C or IPC group. And during the period of reperfusion, the HR was significantly lower in POESR0, POESR30and POESR60groups than in S, C or IPC group. Compared to S group, the MAP and RPP were significantly decreased in C, IPC, POESI15, POESR0, POESR30and POESR60goups during the periods of both ischemia an reperfusion. Compared to IPC group, the number of rats suffering ischemic arrhythmia and arrhythmia score were significantly increased in C, POESI15, POESR0, POESR30and POESR60groups. Comparing to C group, the number of rats suffering reperfusion ventricular arrhythmia and arrhythmia score were significantly decreased in IPC, POESI15and POESR0groups.
The IS%and serum concentrations of cTnI and CK-MB were significantly higher in C group than in IPC, POESI15, POESR0, POESR30and POESR60groups. Compared to IPC group, the IS%was significantly increased in POESI15, POESR0, POESR30and PORSR60groups. Compared to POESI15group, the IS%, serum concentrations of cTnI and CK-MB were significantly increased in POESR60group. Compared to POESR0group, the IS%, serum concentrations of cTnI and CK-MB were increased significantly in POESR60group, but there was no difference in the IS%, secrum concentrations of cTnI and CK-MB between POESR0and POESR30goups. And there was no difference in the IS%and serum concentration of CK-MB between POESR30and POESR60groups.
Compared to S group, the serum concentration of TNF-a at30min,60min and120 min of reperfusion in C group, the serum concentration of HMGB1at60min of reperfusion in C, IPC and POESI15groups, the serum concentration of HMGB1at120min of reperfusion in C, POESR0, POESR30and POESR60groups, the serum concentration of ICAM1at120min of reperfusion in C, POESI15, POESRO, POESR30and POESR60groups, the serum concentration of IL-1at120min of reperfusion in C, IPC, POESRO, POESR30and POESR60groups, the serum concentration of IL-6at120min of reperfusion in C, IPC, POESR30, POESR60groups, the serum concentration of IL-10at120min of reperfusion in POESI15group were all significantly increased. Compared to C group, the serum concentration of TNF-α at30min and60min of reperfusion in both IPC and POESI15groups, the serum concentrations of TNF-α, HMGB1, ICAM1, IL-1and IL-6at120min of reperfusion in IPC, POESI15, POESR0, POESR30and POESR60groups were all significantly decreased. Compared to IPC group, the serum concentration of TNF-α at60min of reperfusion in POESI15group, the serum concentration of TNF-α at120min of reperfusion in POESR60group, the serum concentrations of HMGB1and ICAM1at120min of reperfusion in POESR0, POESR30and POESR60groups were all significantly increased. However, the serum concentration of IL-1at120min of reperfusion in POESI15group, the serum concentration of IL-6at120min of reperfusion in both POESI15and POESR0groups were all significantly decreased. Compared to POESI15group, the serum concentrations of HMGB1and ICAM1at120min of reperfusion in POESR0, POESR30and POESR60groups, the serum concentrations of IL-1, IL-6and TNF-α at120min of reperfusion in POESR60group were all significantly increased. Compared to POESR0group, the serum concentrations of HMGB1, IL-6and TNF-α at120min of reperfusin in POESR60group, the serum concentration of ICAM1at120min of reperfusion in both POESR30and POESR60groups were all significantly increased. The serum concentrations of TNF-α, HMGB1and ICAM1at120min of reperfusion were significantly increased in POESR60group than in POESR30group.
Compared to S group, the ischemic myocardial contents of TNF-α and HMGB1in C group, the non-ischemic myocardial content of TNF-α in both C and POESR60groups, the non-ischemic myocardial content of HMGB1in C group, the ischemic myocardial contents of ICAM1, IL-1and IL-6in C, POESI15, POESR0, POESR30and POESR60groups, the non-ischemic myocardial contents of ICAM1and IL-6in C and POESR60groups, the non-ischemic myocardial content of IL-1and both ischemic and non-ischemic myocardial contents of IL-10in C, IPC, POESI15, POESR0, POESR30 and POESR60groups were all significantly increased. However, the ischemic myocardial content of TNF-a in IPC group, the non-ischemic myocardial content of HMGB1in IPC, POESI15, POESRO and POESR30groups, the non-ischemic myocardial content of ICAM1in IPC, POESI15and POESRO groups, the non-ischemic myocardial content of IL-6in both IPC and POESI15groups were all significantly decreased comparing to S group. Compared to C group, both ischemic and non-ischemic myocardial contents of TNF-a, HMGB1, IL-1and IL-6in IPC, POESI15, POESRO, POESR30and POESR60groups were all significantly decreased, but both ischemic and non-ischemic myocardial contents of IL-10in POESI15group were significantly increased. Compared to IPC group, the ischemic myocardial content of TNF-a in POESI15, POESRO, POESR30and POESR60groups, the non-ischemic myocardial content of HMGB1in POESR60group, the ischemic myocardial content of ICAM1in POESI15, POESRO, POESR30and POESR60groups, the non-ischemic myocardial content of ICAM1and the ischemic myocardial content of IL-6in both POESR30and POESR60groups, the ischemic and non-ischemic myocardial contents of IL-1, the non-ischemic myocardial content of IL-6in POESRO, POESR30and POESR60groups were all significantly increased, but the non-ischemic myocardial content of HMGB1in POESI15group was significantly decreased. Compared to POESI15group, both ischemic and non-ischemic myocardial contents of TNF-a, the non-ischemic myocardial content of ICAM1, ischemic myocardial content of IL-1in both POESR30and POESR60groups, the ischemic myocardial contents of HMGB1and IL-6in POESR60group, the ischemic myocardial content of ICAM1, the non-ischemic myocardial contents of HMGB1, IL-1and IL-6in POESRO, POESR30and POESR60groups were significantly increased, but both ischemic and non-ischemic myocardial contents of IL-10in POESR60group were significantly decreased. Compared to POESRO group, the ischemic myocardial contents of TNF-a, HMGB1, IL-1and IL-6in POESR60group, the non-ischemic myocardial contents of HMGB1, IL-1and IL-6in POESR60group, the ischemic and non-ischemic myocardial contents of ICAMl in both POESR30and POESR60groups were all significantly increased. The ischemic and non-ischemic myocardial contents of ICAM1, IL-6and non-ischemic myocardial content of HMGB1were all significantly higher in POESR60group than in POESR30group.
Part2Experimental study on the protective effect of combined vagus nerve stimulation postconditioning and limb remote ischemic postconditioning against myocardial ischemia reperfusion injury in rats in vivo
Based on the results from the first part of the experiment, we designed this part to oberve whether combine vagus nerve stimulation postconditioning and limb remote ischemic postconditioning would gain an augmented cardioprotective effect.
One hundred and twenty anesthetized male SD rats (weighed290to320g) were randomly allocated into the six groups (n=20in each group):S group, C group, IPC group, POES group, limb remote ischemic postconditioning (LRIPOC) group and combined vagus nerve stimulation postconditioning and limb remote ischemic postconditioning (POES-LRIPOC) group. The procedures of C, IPC and POES groups were as same as those in the first part experiment, and the vagus nerve was stimulated at15min of myocardial ischemia at this part of experiment. In LRIPOC group, the bilateral hind legs were ligatured with an elastic tourniquet at20min of myocardial ischemia. In POES-LRIPOC group, rats received not only the same POES protocol as that of the POES group, but also the same LRIPOC protocol as that of the LRIPOC group. Then, rats in each group were futher randomly allocated into two subgroups. All testing variables in this part were as same as those in the first part of the experiment.
The results showed that rat's body weight, body temperature and baselines of HR, MAP and RPP did not differ among the six groups (P>0.05).
During the periods of ischemia and reperfusion, HR was significantly lower in POES and POES-LRIPOC groups than in S, C or IPC group. During the periods of ischemia and reperfusion, MAP and RPP were significantly lower in C, IPC, POES, LRIPOC and POES-LRIPOC groups than in S group. During the period of ischemia, the number of rats suffering ventricular arrhythmia and the score of arrhythmia were significantly increased in C, POES, LRIPOC and POES-LRIPOC groups comparing to IPC group. During the period of reperfusion, the number of rats suffering ventricular arrhythmia and the score of arrhythmia were significantly reduced in IPC, POES, LRIPOC and POES-LRIPOC groups comparing to C group. And during the period of reperfusion, the number of rats suffering ventricular arrhythmia and the score of arrhythmia were significantly reduced in IPC, POES and POES-LRIPOC groups comparing to LRIPOC group.
Compared to C group, the IS%, serum concentrations of cTnI and CK-MB were significantly decreased in IPC, POES, LRIPOC and POES-LRIPOC groups. Compared to IPC or POES-LRIPOC group, the IS%in POES and LRIPOC groups was significantly increased. Compared to POES group, the IS%and serum concentration of cTnI in LRIPOC group were significantly increased, but the serum concentration of CK-MB was significantly decreased in LRIPOC group. The serum concentrations of cTnI and CK-MB were significantly decreased in IPC and POES-LRIPOC groups than in LRIPOC group.
Compared to S group, the serum concentration of TNF-a at30min of reperfusion in C and LRIPOC groups, the serum concentration of TNF-a at60min and120min of reperfusion in C group, the serum concentration of HMGB1at60min of reperfusion in C, IPC, POES, LRIPOC and POES-LRIPOC groups, the serum concentration of HMGB1at120min of reperfusion in C and LRIPOC groups, the serum concentration of ICAM1at120min of reperfusion in C, POES and LRIPOC groups, the serum concentrations of IL-1and IL-6at120min of reperfusion at C, IPC and LRIPOC groups, the serum concentration of IL-10at120min of reperfusion in POES and POES-LRIPOC groups were all significantly increased, but the serum concentration of TNF-a at60min of reperfusion in IPC and POES-LRIPOC groups, the serum concentration of TNF-a at120min of reperfusion in IPC, POES, LRIPOC and POES-LRIPOC groups were all significantly decreased. Compared to C group, the serum concentration of TNF-a at30min,60min,120min of reperfusion and the serum concentrations of HMGB1, ICAM1, IL-1, IL-6at120min of reperfusion in IPC, POES, LRIPOC and POES-LRIPOC groups, the serum concentration of HMGB1at60min of reperfusion in IPC group were all significantly decreased, but the serum concentration of IL-10at120min of reperfusion in POES-LRIPOC group was significantly increased. Compared to IPC group, the serum concentration of TNF-a at60min of reperfusion in POES and LRIPOC groups, the serum concentrations of HMGB1and ICAM1at120min of reperfusion in LRIPOC group were all significantly increased, but the serum concentrations of IL-1and IL-6in POES and POES-LRIPOC groups were all significantly decreased. Compared to POES group, the serum concentration of TNF-a at60min of reperfusion, the serum concentrations of HMGB1, ICAM1, IL-1and IL-6at120min of reperfusion in LRIPOC group were all significantly increased, but the serum concentration of ICAM1in POES-LRIPOC group was significantly decreased. The serum concentrations of TNF-a at30min,60min and120min of reperfusion, the serum concentrations of HMGB1, ICAM1, IL-1and IL-6at120min of reperfusion were significantly decreased in POES-LRIPOC group than in LRIPOC group.
Compared to S group, the ischemic myocardial contents of TNF-a and HMGB1, the non-ischemic myocardial contents of TNF-a, HMGB1and ICAM1in C group, the ischemic myocardial content of ICAM1in C, POES, LRIPOC and POES-LRIPOC groups, the ischemic myocardial contents of IL-1and IL-6in C, POES and LRIPOC groups, the ischemic myocardial content of IL-10, the non-ischemic myocardial contents of IL-1and IL-10in C, IPC, POES, LRIPOC and POES-LRIPOC groups, the non-ischemic myocardial content of IL-6in C and LRIPOC groups were all significantly increased, but the ischemic myocardial content of TNF-a in IPC and POES-LRIPOC groups, the non-ischemic myocardial content of HMGB1in IPC, POES, LRIPOC and POES-LRIPOC groups, the non-ischemic myocardial contents of ICAM1and IL-6in IPC, POES and POES-LRIPOC groups were all significantly decreased. Compared to C group, the ischemic and non-ischemic myocardial contents of TNF-a, HMGB1, ICAM1, IL-1and IL-6in IPC, POES, LRIPOC and POES-LRIPOC groups were all significantly decreased, but the ischemic and non-ischemic myocardial contents of IL-10in POES and POES-LRIPOC groups were significantly increased. Compared to IPC group, the ischemic myocardial contents of TNF-a, ICAM1and IL-1in POES and LRIPOC groups, the ischemic and non-ischemic myocardial contents of IL-10in POES-LRIPOC group, the ischemic myocardial content of IL-6and the non-ischemic myocardial contents of ICAM1, IL-1and IL-6in LRIPOC group were all significantly increased, but the ischemic myocardial content of HMGB1in POES-LRIPOC group, the non-ischemic myocardial content of HMGB1in POES and POES-LRIPOC groups were all significantly decreased. Compared to POES group, the ischemic myocardial contents of TNF-a, ICAM1and IL-1in POES-LRIPOC group, the ischemic myocardial content of IL-10in LRIPOC group were all significantly decreased, but the non-ischemic myocardial content of IL-10in POES-LRIPOC group, the non-ischemic myocardial contents of HMGB1, ICAM1, IL-1and IL-6, ischemic myocardial contents of ICAM1, IL-1and IL-6in LRIPOC group were all significantly increased. Compared to LRIPOC group, the ischemic myocardial contents of TNF-a, ICAM1, IL-1and IL-6, the non-ischemic myocardial contents of HMGB1, ICAM1, IL-1and IL-6in POES-LRIPOC group were all significantly decreased, but the ischemic and non-ischemic myocardial contents of IL-10were significantly increased.
Part3Roles of the PI3K/Akt and JAK/STAT signal pathways in the cardioprotections of vagus nerve stimulation postconditioning and combined vagus nerve stimulation postconditioning and limb remote ischemic postconditioning
The aims of this part of the experiment were to explore the modulating roles of PI3K/Akt and JAK/STAT signal pathways in cardioprotective effects of vagus nerve stimulation postconditioning and combined vagus nerve stimulation postconditioning and limb remote ischemic postconditioning.
Twenty anesthetized male SD rats (weighed290to320g) were randomly equally divided into four groups (n=5in each group):control group, POES group, LRIPOC group and combined POES and LRIPOC group. After60min of reperfusion, the myocardial tissues from the area at risk in the left ventricle and non-ischemic area in the right ventricule were harvested from excised hearts. Total RNA and total protein were extracted from all myocardial samples, respectively. The real time quantitative polymerase chain reaction (RQ-PCR) was used to quantify the mRNA expression of Akt and STAT3genes in all groups. Also, phosphorylated Akt and phosphorylated STAT3in all samples were assessed by Western-blotting technique.
Compared to C group, ischemic and non-ischemic myocardial phosphorylated Akt (p-Akt) and phosphorylated STAT3(p-STAT3) were all significantly increased in POES, LRIPOC and POES-LRIPOC groups. The ischemic and non-ischemic myocardial p-Akt and p-STAT3were significantly increased in POES-LRIPOC group than in POES or LRIPOC group.
The results of RQ-PCR demonstrated that the mRNA expression of ischemic and non-ischemic myocardial Akt and STAT3genes were significantly enhanced in POES-LRIPOC group compared to C group. Also, the mRNA expression of Akt and STAT3genes were significantly higher in POES-LRIPOC group than in POES or LRIPOC group.
Conclusion
Based on the results of all experiments, the following conclusions can be drawn:
1. Vagus nerve stimulation postconditioning performed at15min of myocardial ischemia, the time immediately before myocardial reperfusion,30min of myocardial reperfusion and60min of myocardial reperfusion can all significantly reduce the infarct size, decrease serum concentrations of cTnI and CK-MB during myocardial ischemia reperfusion injury. Moreover, the cardioprotection provided by vagus nerve stimulation postconditioning at60min of myocardial reperfusion is weakest, while the cardioprotection provided by vagus nerve stimulation postconditioning at15min of myocardial ischemia is strongest but still weaker than ischemic preconditioning.
2. Ischemic preconditioning and vagus nerve stimulation postconditioning performed at different time points can all significantly reduce the ventricular arrhythmias during myocardial reperfusion period. Among vagus nerve stimulation postconditionings performed at different time points, vagus nerve stimulation postconditioning at15min of myocardial ischemia can provide the strongest anti-arrhythmic effect.
3. Combined vagus nerve stimulation postconditioning and limb remote ischemic postconditioning can provide a stronger cardioprotection which is comparable to ischemic preconditioning.
4. Ischemc preconditioning, vagus nerve stimulation postconditioning performed at different time points, limb remote ischemic postconditioning and combined vagus nerve stimulation postconditioning and limb remote ischemic postconditioning can all provide cardioprotections by inhibiting inflammation during myocardial ischemia reperfusion injury.
5. Protein phosphorylation upregulation of related genes involved in both PI3K/Akt and JAK/STAT signal pathways mediates the cardioprotections of vagus nerve stimulation postconditioning and limb remote ischemic postconditoning. And the mRNA expression upregulation of related genes involved in both PI3K/Akt and JAK/STAT signal pathways mediates the cardioprotection of combined vagus nerve stimulation postconditioning and limb remote ischemic postconditioning. Also, the protein phosphorylation upregulation of related genes involved in both PI3K/Akt and JAK/STAT signal pathways probably contributes to the cardioprotection of combined vagus nerve stimulation postconditioning and limb remote ischemic postconditioning
引文
[1]World Health Organization. World health statistics 2009 [M]. Geneve:World Health Organization Press,2009:56.
[2]Lloyd-Jones D, Adams RJ, Brown TM, Carnethon M, Dai S, De Simone G, Ferguson TB, et al. Heart disease and stroke statistics--2010 update:a report from the American Heart Association [J]. Circulation,2010,121(7):e46-e215.
[3]Liu L. Cardiovascular diseases in China [J]. Biochem Cell Biol,2007,85(2):157-163.
[4]Murray CJ, Lopez AD. Alternative projections of mortality and disability by cause 1990-2020:Global Burden of Disease Study [J]. Lancet,1997, 349(9064):1498-1504.
[5]Miller TD, Christian TF, Hopfenspirger MR, Hodge DO, Gersh BJ, Gibbons RJ. Infarct size after acute myocardial infarction measured by quantitative tomographic 99mTc sestamibi imaging predicts subsequent mortality [J]. Circulation,1995, 92(3):334-341.
[6]De Hert SG, Preckel B, Hollmann MW, Schlack WS. Drugs mediating myocardial protection [J]. Eur J Anaesthesiol,2009,26(12):985-995.
[7]Yellon DM, Hausenloy DJ. Myocardial reperfusion injury [J]. N Engl J Med,2007, 357(11):1121-1135.
[8]Willerson JT, Watson JT, Hutton I, Templeton GH, Fixler DE. Reduced myocardial reflow and increased coronary vascular resistance following prolonged myocardial ischemia in the dog [J]. Circ Res,1975,36(6):771-781.
[9]Willerson JT, Scales F, Mukherjee A, Platt M, Templeton GH, Fink GS, Buja LM. Abnormal myocardial fluid retention as an early manifestation of ischemic injury [J]. Am J Pathol,1977,87(1):159-188.
[10]Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction:a quantitative review of 23 randomised trials [J]. Lancet,2003,361(9351):13-20.
[11]Jang IS, Park MY, Shin IW, Sohn JT, Lee HK, Chung YK. Ethyl pyruvate has anti-inflammatory and delayed myocardial protective effects after regional ischemia/reperfusion injury [J]. Yonsei Med J,2010,51(6):838-844.
[12]Jin YC, Kim CW, Kim YM, Nizamutdinova IT, Ha YM, Kim JI, Seo HG, et al. Cryptotanshinone, a lipophilic compound of Salvia miltiorrriza root, inhibits TNF-a induced expression of adhesion molecules in HUVEC and attenuates rat myocardial ischemia/reperfusion injury in vivo [J]. Eur J Pharmacol,2009,614(1-3):91-97.
[13]Jennings RB, Sommers HM, Smyth GA, Flack HA, Linn H. Myocardial necrosis induced by temporary occlusion of a coronary artery in the dog [J]. Arch Pathol, 1960,70:68-78.
[14]Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia:a delay of lethal cell injury in ischemic myocardium [J]. Circulation,1986,74(5):1124-1136.
[15]Hausenloy DJ, Tsang A, Mocanu MM, Yellon DM. Ischemic preconditioning protects by activating prosurvival kinases at reperfusion [J]. Am J Physiol Heart Circ Physiol,2005,288(2):H971-H976.
[16]Cokkinos DV, Pantos C. Myocardial protection in man--from research concept to clinical practice [J]. Heart Fail Rev,2007,12(3-4):345-362.
[17]Zhao ZQ, Corvera JS, Halkos ME, Kerendi F, Wang NP, Guyton RA, Vinten-Johansen J. Inhibition of myocardial injury by ischemic postconditioning during reperfusion:comparison with ischemic preconditioning [J]. Am J Physiol Heart Circ Physiol,2003,285(2):H579-H588.
[18]Lie RH, Hasenkam JM, Nielsen TT, Poulsen R, Sloth E. Post-conditioning reduces infarct size in an open-chest porcine acute ischemia-reperfusion model [J]. Acta Anaesthesiol Scand,2008,52(9):1188-1193.
[19]Kin H, Zhao ZQ, Sun HY, Wang NP, Corvera JS, Halkos ME, Kerendi F, et al. Postconditioning attenuates myocardial ischemia-reperfusion injury by inhibiting events in the early minutes of reperfusion [J]. Cardiovasc Res,2004,62(l):74-85.
[20]Sadat U, Walsh SR, Varty K. Cardioprotection by ischemic postconditioning during surgical procedures [J]. Expert Rev Cardiovasc Ther,2008,6(7):999-1006.
[21]Downey JM, Cohen MV. Why do we still not have cardioprotective drugs? [J]. CircJ,2009,73(7):1171-1177.
[22]Kloner RA, Rezkalla SH. Cardiac protection during acute myocardial infarction: where do we stand in 2004? [J]. J Am Coll Cardiol,2004,44(2):276-286.
[23]Zhao ZQ. Postconditioning in reperfusion injury:a status report [J]. Cardiovasc Drugs Ther,2010,24(3):265-279.
[24]Tracey KJ. Reflex control of immunity [J]. Nat Rev Immunol,2009,9(6):418-428.
[25]Zitnik RJ. Treatment of chronic inflammatory diseases with implantable medical devices [J]. Ann Rheum Dis,2011,70 Suppl 1:i67-i70.
[26]Wu W, Lu Z. Loss of anti-arrhythmic effect of vagal nerve stimulation on ischemia-induced ventricular tachyarrhythmia in aged rats [J]. Tohoku J Exp Med, 2011,223(1):27-33.
[27]Lown B, Verrier RL. Neural activity and ventricular fibrillation [J]. N Engl J Med, 1976,294(21):1165-1170.
[28]Katare RG, Ando M, Kakinuma Y, Arikawa M, Handa T, Yamasaki F, Sato T. Vagal nerve stimulation prevents reperfusion injury through inhibition of opening of mitochondrial permeability transition pore independent of the bradycardiac effect [J]. J Thorac Cardiovasc Surg,2009,137(1):223-231.
[29]Mioni C, Bazzani C, Giuliani D, Altavilla D, Leone S, Ferrari A, Minutoli L, et al. Activation of an efferent cholinergic pathway produces strong protection against myocardial ischemia/reperfusion injury in rats [J]. Crit Care Med,2005, 33(11):2621-2628.
[30]Nakayama Y, Miyano H, Shishido T, Inagaki M, Kawada T, Sugimachi M, Sunagawa K. Heart rate-independent vagal effect on end-systolic elastance of the canine left ventricle under various levels of sympathetic tone [J]. Circulation,2001, 104(19):2277-2279.
[31]Ben-Menachem E. Vagus nerve stimulation, side effects, and long-term safety [J]. J Clin Neurophysiol,2001,18(5):415-418.
[32]Howland RH, Shutt LS, Berman SR, Spotts CR, Denko T. The emerging use of technology for the treatment of depression and other neuropsychiatric disorders [J]. Ann Clin Psychiatry,2011,23(1):48-62.
[33]Shuchman M. Approving the vagus-nerve stimulator for depression [J]. N Engl J Med,2007,356(16):1604-1607.
[34]De Ferrari GM, Schwartz PJ. Vagus nerve stimulation:from pre-clinical to clinical application:challenges and future directions [J]. Heart Fail Rev,2011, 16(2):195-203.
[35]Xin P, Zhu W, Li J, Ma S, Wang L, Liu M, Li J, et al. Combined local ischemic postconditioning and remote perconditioning recapitulate cardioprotective effects of local ischemic preconditioning [J]. Am J Physiol Heart Circ Physiol,2010, 298(6):H1819-H1831.
[36]Tamareille S, Mateus V, Ghaboura N, Jeanneteau J, Croue A, Henrion D, Furber A, et al. RISK and SAFE signaling pathway interactions in remote limb ischemic perconditioning in combination with local ischemic postconditioning [J]. Basic Res Cardiol,2011,106(6):1329-1339.
[37]Gonon AT, Jung C, Yang J, Sjoquist PO, Pernow J. The combination of L-arginine and ischaemic post-conditioning at the onset of reperfusion limits myocardial injury in the pig [J]. Acta Physiol (Oxf),2011,201 (2):219-226.
[38]Huang Z, Zhong X, Irwin MG, Ji S, Wong GT, Liu Y, Xia ZY, et al. Synergy of isoflurane preconditioning and propofol postconditioning reduces myocardial reperfusion injury in patients [J]. Clin Sci (Lond),2011,121(2):57-69.
[39]Menger MD, Vollmar B. Pathomechanisms of ischemia-reperfusion injury as the basis for novel preventive strategies:is it time for the introduction of pleiotropic compounds? [J]. Transplant Proc,2007,39(2):485-488.
[40]Vessey DA, Li L, Kelley M, Karliner JS. Combined sphingosine, S1P and ischemic postconditioning rescue the heart after protracted ischemia [J]. Biochem Biophys Res Commun,2008,375(3):425-429.
[41]Cantley LC. The phosphoinositide 3-kinase pathway [J]. Science,2002, 296(5573):1655-1657.
[42]Tong H, Chen W, Steenbergen C, Murphy E. Ischemic preconditioning activates phosphatidylinositol-3-kinase upstream of protein kinase C [J]. Circ Res,2000, 87(4):309-315.
[43]Uchiyama T, Engelman RM, Maulik N, Das DK. Role of Akt signaling in mitochondrial survival pathway triggered by hypoxic preconditioning [J]. Circulation,2004,109(24):3042-3049.
[44]Tsang A, Hausenloy DJ, Mocanu MM, Yellon DM. Postconditioning:a form of "modified reperfusion" protects the myocardium by activating the phosphatidylinositol 3-kinase-Akt pathway [J]. Circ Res,2004,95(3):230-232.
[45]Malik S, Sharma AK, Bharti S, Nepal S, Bhatia J, Nag TC, Narang R, et al. In vivo cardioprotection by pitavastatin from ischemic-reperfusion injury through suppression of IKK/NF-κB and upregulation of pAkt-e-NOS [J]. J Cardiovasc Pharmacol,2011,58(2):199-206.
[46]Ibacache M, Sanchez G, Pedrozo Z, Galvez F, Humeres C, Echevarria G, Duaso J, et al. Dexmedetomidine preconditioning activates pro-survival kinases and attenuates regional ischemia/reperfusion injury in rat heart [J]. Biochim Biophys Acta,2011,1822(4):537-545.
[47]Birnbaum Y, Long B, Qian J, Perez-Polo JR, Ye Y. Pioglitazone limits myocardial infarct size, activates Akt, and upregulates cPLA2 and COX-2 in a PPAR-gamma-independent manner [J]. Basic Res Cardiol,2011,106(3):431-446.
[48]Yellon DM, Downey JM. Preconditioning the myocardium:from cellular physiology to clinical cardiology [J]. Physiol Rev,2003,83(4):1113-1151.
[49]Krieg T, Qin Q, Philipp S, Alexeyev MF, Cohen MV, Downey JM. Acetylcholine and bradykinin trigger preconditioning in the heart through a pathway that includes Akt and NOS [J]. Am J Physiol Heart Circ Physiol,2004,287(6):H2606-H2611.
[50]Negoro S, Kunisada K, Tone E, Funamoto M, Oh H, Kishimoto T, Yamauchi-Takihara K. Activation of JAK/STAT pathway transduces cytoprotective signal in rat acute myocardial infarction [J]. Cardiovasc Res,2000,47(4):797-805.
[51]Otani H. Ischemic preconditioning:from molecular mechanisms to therapeutic opportunities [J]. Antioxid Redox Signal,2008,10(2):207-247.
[52]Tarnavski O. Mouse surgical models in cardiovascular research [J]. Methods Mol Biol,2009,573:115-137.
[53]Peart JN, Gross GJ. Cardioprotection following adenosine kinase inhibition in rat hearts [J]. Basic Res Cardiol,2005,100(4):328-336.
[54]Kawada T, Yamazaki T, Akiyama T, Kitagawa H, Shimizu S, Mizuno M, Li M, et al. Vagal stimulation suppresses ischemia-induced myocardial interstitial myoglobin release [J]. Life Sci,2008,83(13-14):490-495.
[55]Kloner RA, Dow J, Bhandari A. Postconditioning markedly attenuates ventricular arrhythmias after ischemia-reperfusion [J]. J Cardiovasc Pharmacol Ther,2006, 11(1):55-63.
[56]Oozawa S, Mori S, Kanke T, Takahashi H, Liu K, Tomono Y, Asanuma M, et al. Effects of HMGB1 on ischemia-reperfusion injury in the rat heart [J]. Circ J,2008, 72(7):1178-1184.
[57]Lim SY, Davidson SM, Hausenloy DJ, Yellon DM. Preconditioning and postconditioning:the essential role of the mitochondrial permeability transition pore [J]. Cardiovasc Res,2007,75(3):530-535.
[58]Groban L, Vernon JC, Butterworth J. Intrathecal morphine reduces infarct size in a rat model of ischemia-reperfusion injury [J]. Anesth Analg,2004,98(4):903-909.
[59]Turan NN, Basgut B, Aypar E, Ark M, Iskit AB, Cakici I. Chemical preconditioning effect of 3-nitropropionic acid in anesthetized rat heart [J]. Life Sci,2008, 82(17-18):928-933.
[60]Chiari PC, Bienengraeber MW, Pagel PS, Krolikowski JG, Kersten JR, Warltier DC. Isoflurane protects against myocardial infarction during early reperfusion by activation of phosphatidylinositol-3-kinase signal transduction:evidence for anesthetic-induced postconditioning in rabbits [J]. Anesthesiology,2005, 102(1):102-109.
[61]Stumpner J, Redel A, Kellermann A, Lotz CA, Blomeyer CA, Smul TM, Kehl F, et al. Differential role of Pim-1 kinase in anesthetic-induced and ischemic preconditioning against myocardial infarction [J]. Anesthesiology,2009, 111(6):1257-1264.
[62]Peoples GE, McLennan PL, Howe PR, Groeller H. Fish oil reduces heart rate and oxygen consumption during exercise [J]. J Cardiovasc Pharmacol,2008, 52(6):540-547.
[63]Pourkhalili K, Hajizadeh S, Tiraihi T, Akbari Z, Esmailidehaj M, Bigdeli MR, Khoshbaten A. Ischemia and reperfusion-induced arrhythmias:role of hyperoxic preconditioning [J]. J Cardiovasc Med (Hagerstown),2009,10(8):635-642.
[64]Ferrera R, Benhabbouche S, Bopassa JC, Li B, Ovize M. One hour reperfusion is enough to assess function and infarct size with TTC staining in Langendorff rat model [J]. Cardiovasc Drugs Ther,2009,23(4):327-331.
[65]刘万里,薛茜,曹明芹,马金风.用SPSS实现完全随机设计多组比较秩和检验的多重比较[J].地方病通报,2007,22(2)：27-29.
[66]颜虹,徐勇勇,赵耐青.医学统计学[M].北京：人民卫生出版社,2005：269.
[67]Guerra MS, Roncon-Albuquerque RJ, Lourenco AP, Falcao-Pires I, Cibrao-Coutinho P, Leite-Moreira AF. Remote myocardium gene expression after 30 and 120 min of ischaemia in the rat [J]. Exp Physiol,2006,91(2):473-480.
[68]Wysoczynski M, Shin DM, Kucia M, Ratajczak MZ. Selective upregulation of interleukin-8 by human rhabdomyosarcomas in response to hypoxia:therapeutic implications [J]. Int J Cancer,2010,126(2):371-381.
[69]Weman SM, Karhunen PJ, Penttila A, Jarvinen AA, Salminen US. Reperfusion injury associated with one-fourth of deaths after coronary artery bypass grafting [J]. Ann Thorac Surg,2000,70(3):807-812.
[70]Moore GW, Hutchins GM. Coronary artery bypass grafts in 109 autopsied patients. Statistical analysis of graft and anastomosis patency and regional myocardial injury [J]. JAMA,1981,246(16):1785-1789.
[71]Bulkely BH, Hutchins GM. Myocardial consequences of coronary artery bypass graft surgery. The paradox of necrosis in areas of revascularization [J]. Circulation, 1977,56(6):906-913.
[72]Diaz RJ, Wilson GJ. Studying ischemic preconditioning in isolated cardiomyocyte models [J]. Cardiovasc Res,2006,70(2):286-296.
[73]Hausenloy DJ, Yellon DM. Preconditioning and postconditioning:underlying mechanisms and clinical application [J]. Atherosclerosis,2009,204(2):334-341.
[74]Kin H, Zhao ZQ, Sun HY, Wang NP, Corvera JS, Halkos ME, Kerendi F, et al. Postconditioning attenuates myocardial ischemia-reperfusion injury by inhibiting events in the early minutes of reperfusion [J]. Cardiovasc Res,2004,62(1):74-85.
[75]Kilgore KS, Friedrichs GS, Homeister JW, Lucchesi BR. The complement system in myocardial ischaemia/reperfusion injury [J]. Cardiovasc Res,1994,28(4):437-444.
[76]Frangogiannis NG, Smith CW, Entman ML. The inflammatory response in myocardial infarction [J]. Cardiovasc Res,2002,53(1):31-47.
[77]Jolly SR, Kane WJ, Hook BG, Abrams GD, Kunkel SL, Lucchesi BR. Reduction of myocardial infarct size by neutrophil depletion:effect of duration of occlusion [J]. Am Heart J,1986,112(4):682-690.
[78]Entman ML, Smith CW. Postreperfusion inflammation:a model for reaction to injury in cardiovascular disease [J]. Cardiovasc Res,1994,28(9):1301-1311.
[79]Crawford MH, Grover FL, Kolb WP, Mcmahan CA, Orourke RA, Mcmanus LM, Pinckard RN. Complement and neutrophil activation in the pathogenesis of ischemic myocardial injury [J]. Circulation,1988,78(6):1449-1458.
[80]Gao XM, Liu Y, White D, Su Y, Drew BG, Bruce CR, Kiriazis H, et al. Deletion of macrophage migration inhibitory factor protects the heart from severe ischemia-reperfusion injury:a predominant role of anti-inflammation [J]. J Mol Cell Cardiol,2011,50(6):991-999.
[81]Birdsall HH, Green DM, Trial J, Youker KA, Burns AR, Mackay CR, Larosa GJ, et al. Complement C5a, TGF-β1, and MCP-1, in sequence, induce migration of monocytes into ischemic canine myocardium within the first one to five hours after reperfusion [J]. Circulation,1997,95(3):684-692.
[82]Dhalla NS, Elmoselhi AB, Hata T, Makino N. Status of myocardial antioxidants in ischemia-reperfusion injury [J]. Cardiovasc Res,2000,47(3):446-456.
[83]Velasco CE, Turner M, Inagami T, Atkinson JB, Virmani R, Jackson EK, Murray JJ, et al. Reperfusion enhances the local release of endothelin after regional myocardial ischemia [J]. Am Heart J,1994,128(3):441-451.
[84]Engler RL, Dahlgren MD, Morris DD, Peterson MA, Schmid-Schonbein GW. Role of leukocytes in response to acute myocardial ischemia and reflow in dogs [J]. Am J Physiol,1986,251(2 Pt 2):H314-H323.
[85]Montecucco F, Lenglet S, Braunersreuther V, Pelli G, Pellieux C, Montessuit C, Lerch R, et al. Single administration of the CXC chemokine-binding protein Evasin-3 during ischemia prevents myocardial reperfusion injury in mice [J]. Arterioscler Thromb Vasc Biol,2010,30(7):1371-1377.
[86]Babior BM. The respiratory burst of phagocytes [J]. J Clin Invest,1984, 73(3):599-601.
[87]Schulz R, Aker S, Belosjorow S, Heusch G. TNFa in ischemia/reperfusion injury and heart failure [J]. Basic Res Cardiol,2004,99(1):8-11.
[88]Friedrichs GS, Swillo RE, Jow B, Bridal T, Numann R, Warner LM, Killar LM, et al. Sphingosine modulates myocyte electrophysiology, induces negative inotropy, and decreases survival after myocardial ischemia [J]. J Cardiovasc Pharmacol,2002, 39(1):18-28.
[89]Skyschally A, Gres P, van Caster P, van de Sand A, Boengler K, Schulz R, Heusch G. Reduced calcium responsiveness characterizes contractile dysfunction following coronary microembolization [J]. Basic Res Cardiol,2008,103(6):552-559.
[90]Kimura H, Shintani-Ishida K, Nakajima M, Liu S, Matsumoto K, Yoshida K. Ischemic preconditioning or p38 MAP kinase inhibition attenuates myocardial TNF a production and mitochondria damage in brief myocardial ischemia [J]. Life Sci, 2006,78(17):1901-1910.
[91]Sun M, Dawood F, Wen WH, Chen M, Dixon I, Kirshenbaum LA, Liu PP. Excessive tumor necrosis factor activation after infarction contributes to susceptibility of myocardial rupture and left ventricular dysfunction [J]. Circulation, 2004,110(20):3221-3228.
[92]Hayashidani S, Tsutsui H, Ikeuchi M, Shiomi T, Matsusaka H, Kubota T, Imanaka-Yoshida K, et al. Targeted deletion of MMP-2 attenuates early LV rupture and late remodeling after experimental myocardial infarction [J]. Am J Physiol Heart Circ Physiol,2003,285(3):H1229-H1235.
[93]Hu X, Cui B, Zhou X, Xu C, Lu Z, Jiang H. Ethyl pyruvate reduces myocardial ischemia and reperfusion injury by inhibiting high mobility group box 1 protein in rats [J]. Mol Biol Rep,2012,39(1):227-231.
[94]Andersson U, Wang H, Palmblad K, Aveberger AC, Bloom O, Erlandsson-Harris H, Janson A, et al. High mobility group 1 protein (HMG-1) stimulates proinflammatory cytokine synthesis in human monocytes [J]. J Exp Med,2000,192(4):565-570.
[95]Entman ML, Youker K, Shappell SB, Siegel C, Rothlein R, Dreyer WJ, Schmalstieg FC, et al. Neutrophil adherence to isolated adult canine myocytes. Evidence for a CD18-dependent mechanism [J]. J Clin Invest,1990,85(5):1497-1506.
[96]Smith CW, Entman ML, Lane CL, Beaudet AL, Ty Ti, Youker K, Hawkins HK, et al. Adherence of neutrophils to canine cardiac myocytes in vitro is dependent on intercellular adhesion molecule-1 [J]. J Clin Invest,1991,88(4):1216-1223.
[97]Bujak M, Frangogiannis NG. The role of IL-1 in the pathogenesis of heart disease [J]. Arch Immunol Ther Exp (Warsz),2009,57(3):165-176.
[98]Suzuki K, Murtuza B, Smolenski RT, Sammut IA, Suzuki N, Kaneda Y, Yacoub MH. Overexpression of interleukin-1 receptor antagonist provides cardioprotection against ischemia-reperfusion injury associated with reduction in apoptosis [J]. Circulation,2001,104(12 Suppl 1):I303-I308.
[99]Smart N, Mojet MH, Latchman DS, Marber MS, Duchen MR, Heads RJ. IL-6 induces PI 3-kinase and nitric oxide-dependent protection and preserves mitochondrial function in cardiomyocytes [J]. Cardiovasc Res,2006,69(1):164-177.
[100]Andersson J. The inflammatory reflex—introduction [J]. J Intern Med,2005, 257(2):122-125.
[101]Johnston GR, Webster NR. Cytokines and the immunomodulatory function of the vagus nerve [J]. Br J Anaesth,2009,102(4):453-462.
[102]Borovikova LV, Ivanova S, Zhang M, Yang H, Botchkina GI, Watkins LR, Wang H, et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin [J]. Nature,2000,405(6785):458-462.
[103]Zhou Y, Zuo X, Li Y, Wang Y, Zhao H, Xiao X. Nicotine inhibits tumor necrosis factor-a induced IL-6 and IL-8 secretion in fibroblast-like synoviocytes from patients with rheumatoid arthritis [J]. Rheumatol Int,2012,32(1):97-104.
[104]Meregnani J, Clarencon D, Vivier M, Peinnequin A, Mouret C, Snniger V, Picq C, et al. Anti-inflammatory effect of vagus nerve stimulation in a rat model of inflammatory bowel disease [J]. Auton Neurosci,2011,160(1-2):82-89.
[105]Bernik TR, Friedman SG, Ochani M, Diraimo R, Susarla S, Czura CJ, Tracey KJ. Cholinergic antiinflammatory pathway inhibition of tumor necrosis factor during ischemia reperfusion [J]. J Vasc Surg,2002,36(6):1231-1236.
[106]Uemura K, Zheng C, Li M, Kawada T, Sugimachi M. Early short-term vagal nerve stimulation attenuates cardiac remodeling after reperfused myocardial infarction [J]. J Card Fail,2010,16(8):689-699.
[107]Bolognese L, Cerisano G. Early predictors of left ventricular remodeling after acute myocardial infarction [J]. Am Heart J,1999,138(2 Pt 2):S79-S83.
[108]Hearse DJ. Reperfusion of the ischemic myocardium [J]. J Mol Cell Cardiol,1977, 9(8):605-616.
[109]Cramer JA, Fisher R, Ben-Menachem E, French J, Mattson RH. New antiepileptic drugs:comparison of key clinical trials [J]. Epilepsia,1999,40(5):590-600.
[110]The Vagus Nerve Stimulation Study Group. A randomized controlled trial of chronic vagus nerve stimulation for treatment of medically intractable seizures [J]. Neurology,1995,45(2):224-230.
[111]Ben-Menachem E, Hellstrom K, Waldton C, Augustinsson LE. Evaluation of refractory epilepsy treated with vagus nerve stimulation for up to 5 years [J]. Neurology,1999,52(6):1265-1267.
[112]DeGiorgio CM, Schachter SC, Handforth A, Salinsky M, Thompson J, Uthman B, Reed R, et al. Prospective long-term study of vagus nerve stimulation for the treatment of refractory seizures [J]. Epilepsia,2000,41(9):1195-1200.
[113]Morris GR, Mueller WM. Long-term treatment with vagus nerve stimulation in patients with refractory epilepsy. The Vagus Nerve Stimulation Study Group E01-E05 [J]. Neurology,1999,53(8):1731-1735.
[114]Andreka G, Vertesaljai M, Szantho G, Font G, Piroth Z, Fontos G, Juhasz ED, et al. Remote ischaemic postconditioning protects the heart during acute myocardial infarction in pigs [J]. Heart,2007,93(6):749-752.
[115]Bφtker HE, Kharbanda R, Schmidt MR, Bφttcher M, Kaltoft AK, Terkelsen CJ, Munk K, et al. Remote ischaemic conditioning before hospital admission, as a complement to angioplasty, and effect on myocardial salvage in patients with acute myocardial infarction:a randomised trial [J]. Lancet,2010,375(9716):727-734.
[116]Gritsopoulos G, Iliodromitis EK, Zoga A, Farmakis D, Demerouti E, Papalois A, Paraskevaidis IA, et al. Remote postconditioning is more potent than classic postconditioning in reducing the infarct size in anesthetized rabbits [J]. Cardiovasc Drugs Ther,2009,23(3):193-198.
[117]Schmidt MR, Smerup M, Konstantinov IE, Shimizu M, Li J, Cheung M, White PA, et al. Intermittent peripheral tissue ischemia during coronary ischemia reduces myocardial infarction through a KATP-dependent mechanism:first demonstration of remote ischemic preconditioning [J]. Am J Physiol Heart Circ Physiol,2007, 292(4):H1883-H1890.
[118]Hu X, Jiang H, Ma F, Xu C, Bo C, Wen H, Wu B, et al. Similarities between ischemic preconditioning and postconditioning in myocardial ischemia/reperfusion injury [J]. Int J Cardiol,2010,144(1):135-136.
[119]Manintveld OC, Hekkert ML, van der Ploeg NT, Verdouw PD, Duncker DJ. Interaction between pre- and postconditioning in the in vivo rat heart [J]. Exp Biol Med (Maywood),2009,234(11):1345-1354.
[120]Patten RD, Hall-Porter MR. Small animal models of heart failure:development of novel therapies, past and present [J]. Circ Heart Fail,2009,2(2):138-144.
[121]Wu YN, Yu H, Zhu XH, Yuan HJ, Kang Y, Jiao JJ, Gao WZ, et al. Noninvasive delayed limb ischemic preconditioning attenuates myocardial ischemia-reperfusion injury in rats by a mitochondrial K(ATP) channel-dependent mechanism [J]. Physiol Res,2011,60(2):271-279.
[122]Zatta AJ, Kin H, Lee G, Wang N, Jiang R, Lust R, Reeves JG, et al. Infarct-sparing effect of myocardial postconditioning is dependent on protein kinase C signalling [J]. Cardiovasc Res,2006,70(2):315-324.
[123]Ferrera R, Larese A, Berthod F, Guidollet J, Rodriguez C, Dureau G, Dittmar A. Quantitative reduction of MTT by hearts biopsies in vitro is an index of viability [J]. J Mol Cell Cardiol,1993,25(9):1091-1099.
[124]Schwarz ER, Somoano Y, Hale SL, Kloner RA. What is the required reperfusion period for assessment of myocardial infarct size using triphenyltetrazolium chloride staining in the rat? [J]. J Thromb Thrombolysis,2000,10(2):181-187.
[125]Fruman DA, Cantley LC. Phosphoinositide 3-kinase in immunological systems [J]. Semin Immunol,2002,14(1):7-18.
[126]Coffer PJ, Woodgett JR. Molecular cloning and characterisation of a novel putative protein-serine kinase related to the cAMP-dependent and protein kinase C families [J]. Eur J Biochem,1991,201(2):475-481.
[127]Hers I, Vincent EE, Tavare JM. Akt signalling in health and disease [J]. Cell Signal, 2011,23(10):1515-1527.
[128]Altomare DA, Guo K, Cheng JQ, Sonoda G, Walsh K, Testa JR. Cloning, chromosomal localization and expression analysis of the mouse Akt2 oncogene [J]. Oncogene,1995, 11(6):1055-1060.
[129]Altomare DA, Lyons GE, Mitsuuchi Y, Cheng JQ, Testa JR. Akt2 mRNA is highly expressed in embryonic brown fat and the AKT2 kinase is activated by insulin [J]. Oncogene,1998,16(18):2407-2411.
[130]Hemmings BA. Akt signaling:linking membrane events to life and death decisions [J]. Science,1997,275(5300):628-630.
[131]Downward J. Mechanisms and consequences of activation of protein kinase B/Akt [J]. Curr Opin Cell Biol,1998,10(2):262-267.
[132]Camper-Kirby D, Welch S, Walker A, Shiraishi I, Setchell KD, Schaefer E, Kajstura J, et al. Myocardial Akt activation and gender:increased nuclear activity in females versus males [J]. Circ Res,2001,88(10):1020-1027.
[133]Andjelkovic M, Jakubowicz T, Cron P, Ming XF, Han JW, Hemmings BA. Activation and phosphorylation of a pleckstrin homology domain containing protein kinase (RAC-PK/PKB) promoted by serum and protein phosphatase inhibitors [J]. Proc Natl Acad Sci U S A,1996,93(12):5699-5704.
[134]Brazil DP, Yang Z.Z, Hemmings BA. Advances in protein kinase B signalling: AKTion on multiple fronts [J]. Trends Biochem Sci,2004,29(5):233-242.
[135]Brazil DP, Park J, Hemmings BA. PKB binding proteins. Getting in on the Akt [J]. Cell,2002,111(3):293-303.
[136]Shiojima I, Walsh K. Role of Akt signaling in vascular homeostasis and angiogenesis [J]. Circ Res,2002,90(12):1243-1250.
[137]Vivanco I, Sawyers CL. The phosphatidylinositol 3-Kinase AKT pathway in human cancer [J]. Nat Rev Cancer,2002,2(7):489-501.
[138]Woodgett JR. Recent advances in the protein kinase B signaling pathway [J]. Curr Opin Cell Biol,2005,17(2):150-157.
[139]Dufour C, Holy X, Marie PJ. Transforming growth factor-β prevents osteoblast apoptosis induced by skeletal unloading via PI3K/Akt, Bcl-2, and phospho-Bad signaling [J]. Am J Physiol Endocrinol Metab,2008,294(4):E794-E801.
[140]Jones RG, Saibil SD, Pun JM, Elford AR, Bonnard M, Pellegrini M, Arya S, et al. NF-κB couples protein kinase B/Akt signaling to distinct survival pathways and the regulation of lymphocyte homeostasis in vivo [J]. J Immunol,2005, 175(6):3790-3799.
[141]Tsang A, Hausenloy DJ, Mocanu MM, Carr RD, Yellon DM. Preconditioning the diabetic heart:the importance of Akt phosphorylation [J]. Diabetes,2005, 54(8):2360-2364.
[142]Bopassa JC, Ferrera R, Gateau-Roesch O, Couture-Lepetit E, Ovize M. PI 3-kinase regulates the mitochondrial transition pore in controlled reperfusion and postconditioning [J]. Cardiovasc Res,2006,69(1):178-185.
[143]Aggarwal BB, Kunnumakkara AB, Harikumar KB, Gupta SR, Tharakan ST, Koca C, Dey S, et al. Signal transducer and activator of transcription-3, inflammation, and cancer:how intimate is the relationship? [J]. Ann N Y Acad Sci,2009, 1171:59-76.
[144]Hilfiker-Kleiner D, Hilfiker A, Fuchs M, Kaminski K, Schaefer A, Schieffer B, Hillmer A, et al. Signal transducer and activator of transcription 3 is required for myocardial capillary growth, control of interstitial matrix deposition, and heart protection from ischemic injury [J]. Circ Res,2004,95(2):187-195.
[145]Snyder M, Huang XY, Zhang JJ. Identification of novel direct Stat3 target genes for control of growth and differentiation [J]. J Biol Chem,2008,283(7):3791-3798.
[146]Meldrum DR. Tumor necrosis factor in the heart [J]. Am J Physiol,1998,274(3 Pt 2):R577-R595.
[147]Dawn B, Xuan YT, Guo Y, Rezazadeh A, Stein AB, Hunt G, Wu WJ, et al. IL-6 plays an obligatory role in late preconditioning via JAK-STAT signaling and upregulation of iNOS and COX-2 [J]. Cardiovasc Res,2004,64(1):61-71.
[148]Ananthakrishnan R, Hallam K, Li Q, Ramasamy R. JAK-STAT pathway in cardiac ischemic stress [J]. Vascul Pharmacol,2005,43(5):353-356.
[149]Osugi T, Oshima Y, Fujio Y, Funamoto M, Yamashita A, Negoro S, Kunisada K, et al. Cardiac-specific activation of signal transducer and activator of transcription 3 promotes vascular formation in the heart [J]. J Biol Chem,2002,277(8):6676-6681.
[150]Hattori R, Maulik N, Otani H, Zhu L, Cordis G, Engelman RM, Siddigui MA, et al. Role of STAT3 in ischemic preconditioning [J]. J Mol Cell Cardiol,2001, 33(11):1929-1936.
[151]Smith RM, Suleman N, Lacerda L, Opie LH, Akira S, Chien KR, Sack MN. Genetic depletion of cardiac myocyte STAT-3 abolishes classical preconditioning [J]. Cardiovasc Res,2004,63(4):611-616.
[152]Uemura K, Li M, Tsutsumi T, Yamazaki T, Kawada T, Kamiya A, Inagaki M, et al. Efferent vagal nerve stimulation induces tissue inhibitor of metalloproteinase-1 in myocardial ischemia-reperfusion injury in rabbit [J]. Am J Physiol Heart Circ Physiol,2007,293(4):H2254-H2261.
[153]Xiong J, Xue FS, Yuan YJ, Wang Q, Liao X, Wang WL. Cholinergic anti-inflammatory pathway:a possible approach to protect against myocardial ischemia reperfusion injury [J]. Chin Med J (Engl),2010,123(19):2720-2726.
[154]Steffens S, Montecucco F, Mach F. The inflammatory response as a target to reduce myocardial ischaemia and reperfusion injury [J]. Thromb Haemost,2009, 102(2):240-247.
[155]Li C, Gao Y, Tian J, Shen J, Xing Y, Liu Z. Sophocarpine administration preserves myocardial function from ischemia-reperfusion in rats via NF-κB inactivation [J]. J Ethnopharmacol,2011,135(3):620-625.
[156]Tsao PS, Aoki N, Lefer DJ, Johnson G, Lefer AM. Time course of endothelial dysfunction and myocardial injury during myocardial ischemia and reperfusion in the cat [J]. Circulation,1990,82(4):1402-1412.
[157]Liang F, Gao E, Tao L, Liu H, Qu Y, Christopher TA, Lopez BL, et al. Critical timing of L-arginine treatment in post-ischemic myocardial apoptosis-role of NOS isoforms [J]. Cardiovasc Res,2004,62(3):568-577.
[158]Zimmerman J, Fromm R, Meyer D, Boudreaux A, Wun CC, Smalling R, Davis B, et al. Diagnostic marker cooperative study for the diagnosis of myocardial infarction [J]. Circulation,1999,99(13):1671-1677.
[159]Howie-Esquivel J, White M. Biomarkers in acute cardiovascular disease [J]. J Cardiovasc Nurs,2008,23(2):124-131.
[160]Tsung JS, Tsung SS. Creatine kinase isoenzymes in extracts of various human skeletal muscles [J]. Clin Chem,1986,32(8):1568-1570.
[161]Mair J. Cardiac troponin I and troponin T:are enzymes still relevant as cardiac markers? [J]. Clin Chim Acta,1997,257(1):99-115.
[162]Newby LK, Rodriguez I, Finkle J, Becher RC, Hicks KA, Hausner E, Chesler R, et al. Troponin measurements during drug development--considerations for monitoring and management of potential cardiotoxicity:an educational collaboration among the Cardiac Safety Research Consortium, the Duke Clinical Research Institute, and the US Food and Drug Administration [J]. Am Heart J,2011, 162(1):64-73.
[163]Thygesen K, Alpert JS, White HD. Universal definition of myocardial infarction [J]. Eur Heart J,2007,28(20):2525-2538.
[164]Babuin L, Jaffe AS. Troponin:the biomarker of choice for the detection of cardiac injury [J]. CMAJ,2005,173(10):1191-1202.
[165]Antman EM, Tanasijevic MJ, Thompson B, Schactman M, Mccabe CH, Cannon CP, Fischer GA, et al. Cardiac-specific troponin I levels to predict the risk of mortality in patients with acute coronary syndromes [J]. N Engl J Med,1996, 335(18):1342-1349.
[166]Solaro RJ, Arteaga GM. Heart failure, ischemia/reperfusion injury and cardiac troponin [J]. Adv Exp Med Biol,2007,592:191-200.
[167]Huang WH, Lee JF, Wang D, Gou WH, Chang CY, Wei J. Postischemia myocardial injury in coronary artery bypass patients (PP6) [J]. Transplant Proc, 2010,42(3):725-728.
[168]Jeremias A, Gibson CM. Narrative review:alternative causes for elevated cardiac troponin levels when acute coronary syndromes are excluded [J]. Ann Intern Med, 2005,142(9):786-791.
[169]Saenger AK, Jaffe AS. Requiem for a heavyweight:the demise of creatine kinase-MB [J]. Circulation,2008,118(21):2200-2206.
[170]Hu X, Jiang H, Ma F, Xu C, Bo C, Wen H, Wu B, et al. Similarities between ischemic preconditioning and postconditioning in myocardial ischemia/reperfusion injury [J]. Int J Cardiol,2010,144(1):135-136.
[171]Dai AL, Fan LH, Zhang FJ, Yang MJ, Yu J, Wang JK, Fang T, et al. Effects of sevoflurane preconditioning and postconditioning on rat myocardial stunning in ischemic reperfusion injury [J]. J Zhejiang Univ Sci B,2010,11(4):267-274.
[172]Zipes DP, Wellens HJ. Sudden cardiac death [J]. Circulation,1998, 98(21):2334-2351.
[173]Matejikova J, Ravingerova T, Pancza D, Carnicka S, Kolar F. Mitochondrial KATP opening confers protection against lethal myocardial injury and ischaemia-induced arrhythmias in the rat heart via PI3K/Akt-dependent and-independent mechanisms [J]. Can J Physiol Pharmacol,2009,87(12):1055-1062.
[174]Mackins CJ, Kano S, Seyedi N, Schafer U, Reid AC, Machida T, Silver RB, et al. Cardiac mast cell-derived renin promotes local angiotensin formation, norepinephrine release, and arrhythmias in ischemia/reperfusion [J]. J Clin Invest, 2006,116(4):1063-1070.
[175]Dennis SC, Coetzee WA, Cragoe EJ Jr, Opie LH. Effects of proton buffering and of amiloride derivatives on reperfusion arrhythmias in isolated rat hearts. Possible evidence for an arrhythmogenic role of Na(+)-H+ exchange [J]. Circ Res,1990, 66(4):1156-1159.
[176]Wit AL, Janse MJ. Reperfusion arrhythmias and sudden cardiac death:a century of progress toward an understanding of the mechanisms [J]. Circ Res,2001, 89(9):741-743.
[177]Ravingerova T, Matejikova J, Pancza D, Kolar F. Reduced susceptibility to ischemia-induced arrhythmias in the preconditioned rat heart is independent of PI3-kinase/Akt [J]. Physiol Res,2009,58(3):443-447.
[178]Ogawa K, Ikewaki K, Taniguchi I, Takatsuka H, Mori C, Sasaki H, Okazaki F, et al. Mitiglinide, a novel oral hypoglycemic agent, preserves the cardioprotective effect of ischemic preconditioning in isolated perfused rat hearts [J]. Int Heart J, 2007,48(3):337-345.
[179]Das B, Sarkar C. Similarities between ischemic preconditioning and 17β-estradiol mediated cardiomyocyte KATP channel activation leading to cardioprotective and antiarrhythmic effects during ischemia/reperfusion in the intact rabbit heart [J]. J Cardiovasc Pharmacol,2006,47(2):277-286.
[180]Wu ZK, Iivainen T, Pehkonen E, Laurikka J, Tarkka MR. Ischemic preconditioning suppresses ventricular tachyarrhythmias after myocardial revascularization [J]. Circulation,2002,106(24):3091-3096.
[181]Chen Z, Luo H, Zhuang M, Cai L, Su C, Lei Y, Zou J. Effects of ischemic preconditioning on ischemia/reperfusion-induced arrhythmias by upregulatation of connexin 43 expression [J]. J Cardiothorac Surg,2011,6:80.
[182]Danik SB, Liu F, Zhang J, Suk HJ, Morley GE, Fishman GI, Gutstein DE. Modulation of cardiac gap junction expression and arrhythmic susceptibility [J]. Circ Res,2004,95(10):1035-1041.
[183]Koda K, Salazar-Rodriguez M, Corti F, Chan NY, Estephan R, Silver RB, Mochly-Rosen D, et al. Aldehyde dehydrogenase activation prevents reperfusion arrhythmias by inhibiting local renin release from cardiac mast cells [J]. Circulation,2010,122(8):771-781.
[184]Babai L, Papp JG, Parratt JR, Vegh A. The antiarrhythmic effects of ischaemic preconditioning in anaesthetized dogs are prevented by atropine; role of changes in baroreceptor reflex sensitivity [J]. Br J Pharmacol,2002,135(1):55-64.
[185]Zuanetti G, De Ferrari GM, Priori SG, Schwartz PJ. Protective effect of vagal stimulation on reperfusion arrhythmias in cats [J]. Circ Res,1987,61(3):429-435.
[186]Ando M, Katare RG, Kakinuma Y, Zhang D, Yamasaki F, Muramoto K, Sato T. Efferent vagal nerve stimulation protects heart against ischemia-induced arrhythmias by preserving connexin43 protein [J]. Circulation,2005, 112(2):164-170.
[187]Zipes DP, Rubart M. Neural modulation of cardiac arrhythmias and sudden cardiac death [J]. Heart Rhythm,2006,3(1):108-113.
[188]Ng GA, Brack KE, Patel VH, Coote JH. Autonomic modulation of electrical restitution, alternans and ventricular fibrillation initiation in the isolated heart [J]. Cardiovasc Res,2007,73(4):750-760.
[189]Jiang H, Hu X, Lu Z, Wen H, Zhao D, Tang Q, Yang B. Effects of sympathetic nerve stimulation on ischemia-induced ventricular arrhythmias by modulating connexin43 in rats [J]. Arch Med Res,2008,39(7):647-654.
[190]Kawaguchi M, Takahashi M, Hata T, Kashima Y, Usui F, Morimoto H, Izawa A, et al. Inflammasome activation of cardiac fibroblasts is essential for myocardial ischemia/reperfusion injury [J]. Circulation,2011,123(6):594-604.
[191]Black RA, Rauch CT, Kozlosky CJ, Peschon JJ, Slack JL, Wolfson MF, Castner BJ, et al. A metalloproteinase disintegrin that releases tumour-necrosis factor-a from cells [J]. Nature,1997,385(6618):729-733.
[192]Zhang C, Xu X, Potter BJ, Wang W, Kuo L, Michae L, Bagby GL, et al. TNF-a contributes to endothelial dysfunction in ischemia/reperfusion injury [J]. Arterioscler Thromb Vase Biol,2006,26(3):475-480.
[193]Zhang C, Wu J, Xu X, Potter BJ, Gao X. Direct relationship between levels of TNF-α expression and endothelial dysfunction in reperfusion injury [J]. Basic Res Cardiol,2010,105(4):453-464.
[194]Gao X, Zhang H, Belmadani S, Wu J, Xu X, Elford H, Potter BJ, et al. Role of TNF-a-induced reactive oxygen species in endothelial dysfunction during reperfusion injury [J]. Am J Physiol Heart Circ Physiol,2008, 295(6):H2242-H2249.
[195]Yamada S, Maruyama I. HMGB1, a novel inflammatory cytokine [J]. Clin Chim Acta,2007,375(1-2):36-42.
[196]Ulloa L, Messmer D. High-mobility group box 1 (HMGB1) protein:friend and foe [J]. Cytokine Growth Factor Rev,2006,17(3):189-201.
[197]Li W, Sama AE, Wang H. Role of HMGB1 in cardiovascular diseases [J]. Curr Opin Pharmacol,2006,6(2):130-135.
[198]Andrassy M, Volz HC, Igwe JC, Funke B, Eichberger SN, Kaya Z, Buss S, et al. High-mobility group box-1 in ischemia-reperfusion injury of the heart [J]. Circulation,2008,117(25):3216-3226.
[199]Kalawski R, Majewski M, Kaszkowiak E, Wysocki H, Siminiak T. Transcardiac release of soluble adhesion molecules during coronary artery bypass grafting: effects of crystalloid and blood cardioplegia [J]. Chest,2003,123(5):1355-1360.
[200]Metzler B, Mair J, Lercher A, Schaber C, Hintringer F, Pachinger O, Xu Q. Mouse model of myocardial remodelling after ischemia:role of intercellular adhesion molecule-1 [J]. Cardiovasc Res,2001,49(2):399-407.
[201]Murohara T, Kamijikkoku S, Honda T. Increased circulating soluble intercellular adhesion molecule-1 in acute myocardial infarction:a possible predictor of reperfusion ventricular arrhythmias [J]. Crit Care Med,2000,28(6):1861-1864.
[202]Bujak M, Dobaczewski M, Chatila K, Mendoza LH, Li N, Reddy A, Frangogiannis NG. Interleukin-1 receptor type I signaling critically regulates infarct healing and cardiac remodeling [J]. Am J Pathol,2008,173(1):57-67.
[203]Abbate A, Van Tassell BW, Seropian IM, Toldo S, Robati R, Varma A, Salloum FN, et al. Interleukin-1β modulation using a genetically engineered antibody prevents adverse cardiac remodelling following acute myocardial infarction in the mouse [J]. Eur J Heart Fail,2010,12(4):319-322.
[204]Abbate A, Kontos MC, Grizzard JD, Biondi-Zoccai GG, Van Tassell BW, Robati R, Roach LM, et al. Interleukin-1 blockade with anakinra to prevent adverse cardiac remodeling after acute myocardial infarction (Virginia Commonwealth University Anakinra Remodeling Trial [VCU-ART] Pilot study) [J]. Am J Cardiol,2010, 105(10):1371-1377.
[205]Akiyama D, Hara T, Yoshitomi O, Maekawa T, Cho S, Sumikawa K. Postischemic infusion of sivelestat sodium hydrate, a selective neutrophil elastase inhibitor, protects against myocardial stunning in swine [J]. J Anesth,2010,24(4):575-581.
[206]Loubele ST, Spek CA, Leenders P, van Oerle R, Aberson HL, van der Voort D, Hamulyak K, et al. Active site inhibited factor Ⅶa attenuates myocardial ischemia/reperfusion injury in mice [J]. J Thromb Haemost,2009,7(2):290-298.
[207]Sawa Y, Ichikawa H, Kagisaki K, Ohata T, Matsuda H. Interleukin-6 derived from hypoxic myocytes promotes neutrophil-mediated reperfusion injury in myocardium [J]. J Thorac Cardiovasc Surg,1998,116(3):511-517.
[208]Yang Z, Zingarelli B, Szabo C. Crucial role of endogenous interleukin-10 production in myocardial ischemia/reperfusion injury [J]. Circulation,2000, 101(9):1019-1026.
[209]Pasqui AL, Di Renzo M, Maffei S, Pastorelli M, Pompella G, Auteri A, Puccetti L. Pro/Anti-inflammatory cytokine imbalance in postischemic left ventricular remodeling [J]. Mediators Inflamm,2010,2010:974694.
[210]Sabat R, Grutz G, Warszawska K, Kirsch S, Witte E, Wolk K, Geginat J. Biology of interleukin-10 [J]. Cytokine Growth Factor Rev,2010,21(5):331-344.
[211]Hiasa G, Hamada M, Ikeda S, Hiwada K. Ischemic preconditioning and lipopolysaccharide attenuate nuclear factor-κB activation and gene expression of inflammatory cytokines in the ischemia-reperfused rat heart [J]. Jpn Circ J,2001, 65(11):984-990.
[212]Xiong J, Wang Q, Xue FS, Yuan YJ, Li S, Liu JH, Liao X, et al. Comparison of cardioprotective and anti-inflammatory effects of ischemia pre- and postconditioning in rats with myocardial ischemia-reperfusion injury [J]. Inflamm Res,2011,60(6):547-554.
[213]Hausenloy DJ, Yellon DM. The therapeutic potential of ischemic conditioning:an update [J]. Nat Rev Cardiol,2011,8(11):619-629.
[214]Hausenloy DJ, Yellon DM. Remote ischaemic preconditioning:underlying mechanisms and clinical application [J]. Cardiovasc Res,2008,79(3):377-386.
[215]Larsen JR, Aagaard S, Lie RH, Sloth E, Hasenkam JM. Sevoflurane improves myocardial ischaemic tolerance in a closed-chest porcine model [J]. Acta Anaesthesiol Scand,2008,52(10):1400-1410.
[216]Konstantinov IE, Arab S, Kharbanda RK, Li J, Cheung MM, Cherepanov V, Downey GP, et al. The remote ischemic preconditioning stimulus modifies inflammatory gene expression in humans [J]. Physiol Genomics,2004, 19(1):143-150.
[217]Li CM, Zhang XH, Ma XJ, Luo M. Limb ischemic postconditioning protects myocardium from ischemia-reperfusion injury [J]. Scand Cardiovasc J,2006, 40(5):312-317.
[218]Osswald H, Moerike K. Remote conditioning in clinical practice:a type of distant healing? [J]. Cardiology,2011,119(4):214-216.
[219]Pavlov VA, Tracey KJ. The cholinergic anti-inflammatory pathway [J]. Brain Behav Immun,2005,19(6):493-499.
[220]Tracey KJ. The inflammatory reflex [J]. Nature,2002,420(6917):853-859.
[221]Williams DL, Li C, Ha T, Ozment-Skelton T, Kalbfleisch JH, Preiszner J, Brooks L, et al. Modulation of the phosphoinositide 3-kinase pathway alters innate resistance to polymicrobial sepsis [J]. J Immunol,2004,172(1):449-456.
[222]Guha M, Mackman N. The phosphatidylinositol 3-kinase-Akt pathway limits lipopolysaccharide activation of signaling pathways and expression of inflammatory mediators in human monocytic cells [J]. J Biol Chem,2002,277(35):32124-32132.
[223]Fukao T, Koyasu S. PI3K and negative regulation of TLR signaling [J]. Trends Immunol,2003,24(7):358-363.
[224]Li C, Ha T, Kelley J, Gao X, Qiu Y, Kao RL, Browder W, et al. Modulating Toll-like receptor mediated signaling by (1-->3)-β-D-glucan rapidly induces cardioprotection [J]. Cardiovasc Res,2004,61(3):538-547.
[225]Ernst M, Najdovska M, Grail D, Lundgen-May T, Buchert M, Tye H, Matthews VB, et al. STAT3 and STAT1 mediate IL-11-dependent and inflammation-associated gastric tumorigenesis in gpl30 receptor mutant mice [J]. J Clin Invest,2008,118(5):1727-1738.
[226]Wang M, Zhang W, Crisostomo P, Markel T, Meldrum KK, Fu XY, Meldrum DR. Endothelial STAT3 plays a critical role in generalized myocardial proinflammatory and proapoptotic signaling [J]. Am J Physiol Heart Circ Physiol,2007, 293(4):H2101-H2108.
[227]Goodman MD, Koch SE, Fuller-Bicer GA, Butler KL. Regulating RISK:a role for JAK-STAT signaling in postconditioning? [J]. Am J Physiol Heart Circ Physiol, 2008,295(4):H1649-H1656.
[228]Matsui T, Li L, Wu JC, Cook SA, Nagoshi T, Picard MH, Liao R, et al. Phenotypic spectrum caused by transgenic overexpression of activated Akt in the heart [J]. J Biol Chem,2002,277(25):22896-22901.
[229]Shioi T, McMullen JR, Kang PM, Douglas PS, Obata T, Franke TF, Cantley LC, et al. Akt/protein kinase B promotes organ growth in transgenic mice [J]. Mol Cell Biol,2002,22(8):2799-2809.
[230]Malstrom S, Tili E, Kappes D, Ceci JD, Tsichlis PN. Tumor induction by an Lck-MyrAkt transgene is delayed by mechanisms controlling the size of the thymus [J]. Proc Natl Acad Sci U S A,2001,98(26):14967-14972.
[231]Tuttle RL, Gill NS, Pugh W, Lee JP, Koeberlein B, Furth EE, Polonsky KS, et al. Regulation of pancreatic β-cell growth and survival by the serine/threonine protein kinase Aktl/PKBa [J]. Nat Med,2001,7(10):1133-1137.
[232]Bernal-Mizrachi E, Wen W, Stahlhut S, Welling CM, Permutt MA. Islet β cell expression of constitutively active Aktl/PKB a induces striking hypertrophy, hyperplasia, and hyperinsulinemia [J]. J Clin Invest,2001,108(11):1631-1638.
[233]Schwertfeger KL, McManaman JL, Palmer CA, Neville MC, Anderson SM. Expression of constitutively activated Akt in the mammary gland leads to excess lipid synthesis during pregnancy and lactation [J]. J Lipid Res,2003, 44(6):1100-1112.
[234]Datta SR, Brunet A, Greenberg ME. Cellular survival:a play in three Akts [J]. Genes Dev,1999,13(22):2905-2927.
[235]Mangi AA, Noiseux N, Kong D, He H, Rezvani M, Ingwall JS, Dzau VJ. Mesenchymal stem cells modified with Akt prevent remodeling and restore performance of infarcted hearts [J]. Nat Med,2003,9(9):1195-1201.
[236]Tong H, Imahashi K, Steenbergen C, Murphy E. Phosphorylation of glycogen synthase kinase-3β during preconditioning through a phosphatidylinositol-3-kinase-dependent pathway is cardioprotective [J]. Circ Res, 2002,90(4):377-379.
[237]Ban K, Cooper AJ, Samuel S, Bhatti A, Patel M, Izumo S, Penninger JM, et al. Phosphatidylinositol 3-kinase gamma is a critical mediator of myocardial ischemic and adenosine-mediated preconditioning [J]. Circ Res,2008,103(6):643-653.
[238]Kunuthur SP, Mocanu MM, Hemmings BA, Hausenloy DJ, Yellon DM. The Aktl isoform is an essential mediator of ischemic preconditioning [J]. J Cell Mol Med, 2011 [Epub ahead of print].
[239]Hausenloy DJ, Yellon DM. Survival kinases in ischemic preconditioning and postconditioning [J]. Cardiovasc Res,2006,70(2):240-253.
[240]Heusch G, Boengler K, Schulz R. Inhibition of mitochondrial permeability transition pore opening:the Holy Grail of cardioprotection [J]. Basic Res Cardiol, 2010,105(2):151-154.
[241]Juhaszova M, Zorov DB, Kim SH, Pepe S, Fu Q, Fishbein KW, Ziman BD, et al. Glycogen synthase kinase-3β mediates convergence of protection signaling to inhibit the mitochondrial permeability transition pore [J]. J Clin Invest,2004, 113(11):1535-1549.
[242]Li J, Xuan W, Yan R, Tropak MB, Jean-St-Michel E, Liang W, Gladstone R, et al. Remote preconditioning provides potent cardioprotection via PI3K/Akt activation and is associated with nuclear accumulation of β-catenin [J]. Clin Sci (Lond),2011, 120(10):451-462.
[243]Rahman S, Li J, Bopassa JC, Umar S, Iorga A, Partownavid P, Eghbali M. Phosphorylation of GSK-3β mediates intralipid-induced cardioprotection against ischemia/reperfusion injury [J]. Anesthesiology,2011,115(2):242-253.
[244]Fang SJ, Wu XS, Han ZH, Zhang XX, Wang CM, Li XY, Lu LQ, et al. Neuregulin-1 preconditioning protects the heart against ischemia/reperfusion injury through a PI3K/Akt-dependent mechanism [J]. Chin Med J (Engl),2010, 123(24):3597-3604.
[245]Zhou H, Hou SZ, Luo P, Zeng B, Wang JR, Wong YF, Jiang ZH, et al. Ginseng protects rodent hearts from acute myocardial ischemia-reperfusion injury through GR/ER-activated RISK pathway in an endothelial NOS-dependent mechanism [J]. J Ethnopharmacol,2011,135(2):287-298.
[246]Huang MH, Wu Y, Nguyen V, Rastogi S, Mcconnell BK, Wijaya C, Uretsky BF, et al. Heart protection by combination therapy with esmolol and milrinone at late-ischemia and early reperfusion [J]. Cardiovasc Drugs Ther,2011, 25(3):223-232.
[247]Boengler K, Hilfiker-Kleiner D, Drexler H, Heusch G, Schulz R. The myocardial JAK/STAT pathway:from protection to failure [J]. Pharmacol Ther,2008, 120(2):172-185.
[248]Akira S, Nishio Y, Inoue M, Wang XJ, Wei S, Matsusaka T, Yoshida K, et al. Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway [J]. Cell, 1994,77(1):63-71.
[249]Cao X, Tay A, Guy GR, Tan YH. Activation and association of Stat3 with Src in v-Src-transformed cell lines [J]. Mol Cell Biol,1996,16(4):1595-1603.
[250]Vignais ML, Sadowski HB, Watling D, Rogers NC, Gilman M. Platelet-derived growth factor induces phosphorylation of multiple JAK family kinases and STAT proteins [J]. Mol Cell Biol,1996,16(4):1759-1769.
[251]Yu CL, Meyer DJ, Campbell GS, Larner AC, Carter-Su C, Schwartz J, Jove R. Enhanced DNA-binding activity of a Stat3-related protein in cells transformed by the Src oncoprotein [J]. Science,1995,269(5220):81-83.
[252]Giordano V, De Falco G, Chiari R, Quinto I, Pelicci PG, Bartholomew L, Delmastro P, et al. Shc mediates IL-6 signaling by interacting with gp130 and Jak2 kinase [J]. J Immunol,1997,158(9):4097-4103.
[253]Garcia R, Yu CL, Hudnall A, Catlett R, Nelson KL, Smithgall T, Fujita DJ, et al. Constitutive activation of Stat3 in fibroblasts transformed by diverse oncoproteins and in breast carcinoma cells [J]. Cell Growth Differ,1997,8(12):1267-1276.
[254]Lutticken C, Wegenka UM, Yuan J, Buschmann J, Schindler C, Ziemiecki A, Harpur AG, et al. Association of transcription factor APRF and protein kinase Jakl with the interleukin-6 signal transducer gp130 [J]. Science,1994,263(5143):89-92.
[255]Tian SS, Tapley P, Sincich C, Stein RB, Rosen J, Lamb P. Multiple signaling pathways induced by granulocyte colony-stimulating factor involving activation of JAKs, STAT5, and/or STAT3 are required for regulation of three distinct classes of immediate early genes [J]. Blood,1996,88(12):4435-4444.
[256]Migone TS, Lin JX, Cereseto A, Mulloy JC, O'shea JJ, Franchini G, Leonard WJ. Constitutively activated Jak-STAT pathway in T cells transformed with HTLV-I [J]. Science,1995,269(5220):79-81.
[257]Megeney LA, Perry RL, LeCouter JE, Rudnicki MA. bFGF and LIF signaling activates STAT3 in proliferating myoblasts [J]. Dev Genet,1996,19(2):139-145.
[258]Boengler K, Hilfiker-Kleiner D, Heusch G, Schulz R. Inhibition of permeability transition pore opening by mitochondrial STAT3 and its role in myocardial ischemia/reperfusion [J]. Basic Res Cardiol,2010,105(6):771-785.
[259]Bolli R, Stein AB, Guo Y, Wang OL, Rokosh G, Dawn B, Molkentin JD, et al. A murine model of inducible, cardiac-specific deletion of STAT3:its use to determine the role of STAT3 in the upregulation of cardioprotective proteins by ischemic preconditioning [J]. J Mol Cell Cardiol,2011,50(4):589-597.
[260]Tian Y, Zhang W, Xia D, Modi P, Liang D, Wei M. Postconditioning inhibits myocardial apoptosis during prolonged reperfusion via a JAK2-STAT3-Bcl-2 pathway [J]. J Biomed Sci,2011,18:53.
[261]Boengler K, Buechert A, Heinen Y, Roeskes C, Hilfiker-Kleiner D, Heusch G, Schulz R. Cardioprotection by ischemic postconditioning is lost in aged and STAT3-deficient mice [J]. Circ Res,2008,102(1):131-135.
[262]Kelly RF, Lamont KT, Somers S, Hacking D, Lacerda L, Thomas P, Opie LH, et al. Ethanolamine is a novel STAT-3 dependent cardioprotective agent [J]. Basic Res Cardiol,2010,105(6):763-770.
[263]Wang M, Wang Y, Abarbanell A, Tan J, Weil B, Herrmann J, Meldrum DR. Both endogenous and exogenous testosterone decrease myocardial STAT3 activation and SOCS3 expression after acute ischemia and reperfusion [J]. Surgery,2009, 146(2):138-144.
[264]Baker JE, Su J, Hsu A, Shi Y, Zhao M, Strande JL, Fu X, et al. Human thrombopoietin reduces myocardial infarct size, apoptosis, and stunning following ischaemia/reperfusion in rats [J]. Cardiovasc Res,2008,77(1):44-53.
[265]Gross ER, Hsu AK, Gross GJ. The JAK/STAT pathway is essential for opioid-induced cardioprotection:JAK2 as a mediator of STAT3, Akt, and GSK-3β [J]. Am J Physiol Heart Circ Physiol,2006,291(2):H827-H834.
[266]Li X, Mikhalkova D, Gao E, Zhang J, Myers V, Zincarelli C, Lei Y, et al. Myocardial injury after ischemia-reperfusion in mice deficient in Akt2 is associated with increased cardiac macrophage density [J]. Am J Physiol Heart Circ Physiol, 2011,301(5):H1932-H1940.
[267]Pfitzner E, Kliem S, Baus D, Litterst CM. The role of STATs in inflammation and inflammatory diseases [J]. Curr Pharm Des,2004,10(23):2839-2850.
[268]Zhong Z, Wen Z, Darnell JJ. Stat3:a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6 [J]. Science,1994,264(5155):95-98.
[269]Dalwadi H, Krysan K, Heuze-Vourc'H N, Dohadwala M, Elashoff D, Sharma S, Cacalano N, et al. Cyclooxygenase-2-dependent activation of signal transducer and activator of transcription 3 by interleukin-6 in non-small cell lung cancer [J]. Clin Cancer Res,2005, 11(21):7674-7682.
[270]Calvillo L, Vanoli E, Andreoli E, Besana A, Omodeo E, Gnecchi M, Zerbi P, et al. Vagal stimulation, through its nicotinic action, limits infarct size and the inflammatory response to myocardial ischemia and reperfusion [J]. J Cardiovasc Pharmacol,2011,58(5):500-507.
[271]Maroko PR, Kjekshus JK, Sobel BE, Watanabe T, Covell JW, Ross J Jr, Braunwald E. Factors influencing infarct size following experimental coronary artery occlusions [J]. Circulation,1971,43(1):67-82.
[272]Redwood DR, Smith ER, Epstein SE. Coronary artery occlusion in the conscious dog. Effects of alterations in heart rate and arterial pressure on the degree of myocardial ischemia [J]. Circulation,1972,46(2):323-332.
[273]Wu AH, Parsons L, Every NR, Bates ER. Hospital outcomes in patients presenting with congestive heart failure complicating acute myocardial infarction:a report from the Second National Registry of Myocardial Infarction (NRMI-2) [J]. J Am Coll Cardiol,2002,40(8):1389-1394.
[274]Cury RC, Techasith T, Feuchtner G, Dabus G. Cardiovascular disease and stroke in women:role of radiology [J]. AJR Am J Roentgenol,2011,196(2):265-273.
[275]Zhang XH, Lu ZL, Liu L. Coronary heart disease in China [J]. Heart,2008, 94(9):1126-1131.
[276]Gaziano TA, Bitton A, Anand S, Abrahams-Gessel S, Murphy A. Growing epidemic of coronary heart disease in low- and middle-income countries [J]. Curr Probl Cardiol,2010,35(2):72-115.
[277]Nallamothu B, Fox KA, Kennelly BM, Van de Werf F, Gore JM, Steg PG, Granger CB, et al. Relationship of treatment delays and mortality in patients undergoing fibrinolysis and primary percutaneous coronary intervention. The Global Registry of Acute Coronary Events [J]. Heart,2007,93(12):1552-1555.
[278]Armstrong PW, Westerhout CM, Welsh RC. Duration of symptoms is the key modulator of the choice of reperfusion for ST-elevation myocardial infarction [J]. Circulation,2009,119(9):1293-1303.
[279]Vinten-Johansen J. Involvement of neutrophils in the pathogenesis of lethal myocardial reperfusion injury [J]. Cardiovasc Res,2004,61(3):481-497.
[280]Frangogiannis NG, Youker KA, Entman ML. The role of the neutrophil in myocardial ischemia and reperfusion [J]. EXS,1996,76:263-284.
[281]Hatchell DL, Wilson CA, Saloupis P. Neutrophils plug capillaries in acute experimental retinal ischemia [J]. Microvasc Res,1994,47(3):344-354.
[282]Gute DC, Ishida T, Yarimizu K, Korthuis RJ. Inflammatory responses to ischemia and reperfusion in skeletal muscle [J]. Mol Cell Biochem,1998,179(1-2):169-187.
[283]Rezkalla SH, Kloner RA. Coronary no-reflow phenomenon:from the experimental laboratory to the cardiac catheterization laboratory [J]. Catheter Cardiovasc Interv, 2008,72(7):950-957.
[284]Strande JL, Routhu KV, Hsu A, Nicolosi AC, Baker JE. Gadolinium decreases inflammation related to myocardial ischemia and reperfusion injury [J]. J Inflamm (Lond),2009,6:34.
[285]Nicolini FA, Mehta JL, Nichols WW, Donnelly WH, Luostarinen R, Saldeen TG. Leukocyte elastase inhibition and t-PA-induced coronary artery thrombolysis in dogs:beneficial effects on myocardial histology [J]. Am Heart J,1991, 122(5):1245-1251.
[286]Yu X, Kennedy RH, Liu SJ. JAK2/STAT3, not ERK1/2, mediates interleukin-6-induced activation of inducible nitric-oxide synthase and decrease in contractility of adult ventricular myocytes [J]. J Biol Chem,2003, 278(18):16304-16309.
[287]Romson JL, Hook BG, Kunkel SL, Abrams GD, Schork MA, Lucchesi BR. Reduction of the extent of ischemic myocardial injury by neutrophil depletion in the dog [J]. Circulation,1983,67(5):1016-1023.
[288]Jordan JE, Zhao ZQ, Vinten-Johansen J. The role of neutrophils in myocardial ischemia-reperfusion injury [J]. Cardiovasc Res,1999,43(4):860-878.
[289]Takahashi T, Hiasa Y, Ohara Y, Miyazaki S, Ogura R, Miyajima H, Yuba K, et al. Relation between neutrophil counts on admission, microvascular injury, and left ventricular functional recovery in patients with an anterior wall first acute myocardial infarction treated with primary coronary angioplasty [J]. Am J Cardiol, 2007,100(1):35-40.
[290]Dokken BB, La Bonte LR, Davis-Gorman G, Teachey MK, Seaver N, Mcdonagh PF. Glucagon-like peptide-1 (GLP-1), immediately prior to reperfusion, decreases neutrophil activation and reduces myocardial infarct size in rodents [J]. Horm Metab Res,2011,43(5):300-305.
[291]Zhang Y, Sun Q, He B, Xiao J, Wang Z, Sun X. Anti-inflammatory effect of hydrogen-rich saline in a rat model of regional myocardial ischemia and reperfusion [J]. Int J Cardiol,2011,148(1):91-95.
[292]Abdel-Rahman U, Margraf S, Aybek T, Logers T, Bitu-Moreno J, Francischetti I, Kranert T, et al. Inhibition of neutrophil activity improves cardiac function after cardiopulmonary bypass [J]. J Inflamm (Lond),2007,4:21.
[293]Hoffmeyer MR, Scalia R, Ross CR, Jones SP, Lefer DJ. PR-39, a potent neutrophil inhibitor, attenuates myocardial ischemia-reperfusion injury in mice [J]. Am J Physiol Heart Circ Physiol,2000,279(6):H2824-H2828.
[294]Feng Y, Zhao H, Xu X, Buys ES, Raher MJ, Bopassa JC, Thibault H, et al. Innate immune adaptor MyD88 mediates neutrophil recruitment and myocardial injury after ischemia-reperfusion in mice [J]. Am J Physiol Heart Circ Physiol,2008, 295(3):H1311-H1318.
[295]Zerria K, Jerbi E, Hammami S, Maaroufi A, Boubader S, Xiong JP, Arnaout MA, et al. Recombinant integrin CDllb A-domain blocks polymorphonuclear cells recruitment and protects against skeletal muscle inflammatory injury in the rat [J]. Immunology,2006,119(4):431-440.
[296]Baran KW, Nguyen M, McKendall GR, Lambrew CT, Dykstra G, Palmeri ST, Gibbons RJ, et al. Double-blind, randomized trial of an anti-CD 18 antibody in conjunction with recombinant tissue plasminogen activator for acute myocardial infarction:limitation of myocardial infarction following thrombolysis in acute myocardial infarction (LIMIT AMI) study [J]. Circulation,2001, 104(23):2778-2783.
[297]Faxon DP, Gibbons RJ, Chronos NA, Gurbel PA, Sheehan F. The effect of blockade of the CD11/CD 18 integrin receptor on infarct size in patients with acute myocardial infarction treated with direct angioplasty:the results of the HALT-MI study [J]. J Am Coll Cardiol,2002,40(7):1199-1204.
[298]Nathan C. Points of control in inflammation [J]. Nature,2002,420(6917):846-852.
[299]Venkatachalam K, Prabhu SD, Reddy VS, Boylston WH, Valente AJ, Chandrasekar B. Neutralization of interleukin-18 ameliorates ischemia/reperfusion-induced myocardial injury [J]. J Biol Chem,2009, 284(12):7853-7865.
[300]Rudolph V, Rudolph TK, Schopfer FJ, Bonacci G, Woodcock SR, Cole MP, Baker PR, et al. Endogenous generation and protective effects of nitro-fatty acids in a murine model of focal cardiac ischaemia and reperfusion [J]. Cardiovasc Res,2010, 85(1):155-166.
[301]Zhao N, Liu YY, Wang F, Hu BH, Sun K, Chang X, Pan CS, et al. Cardiotonic pills, a compound Chinese medicine, protects ischemia-reperfusion-induced microcirculatory disturbance and myocardial damage in rats [J]. Am J Physiol Heart Circ Physiol,2010,298(4):H1166-H1176.
[302]Cain BS, Meldrum DR, Dinarello CA, Meng X, Joo KS, Banerjee A, Harken AH. Tumor necrosis factor-a and interleukin-1β synergistically depress human myocardial function [J]. Crit Care Med,1999,27(7):1309-1318.
[303]Irwin MW, Mak S, Mann DL, Qu R, Penninger JM, Yan A, Dawood F, et al. Tissue expression and immunolocalization of tumor necrosis factor-a in postinfarction dysfunctional myocardium [J]. Circulation,1999,99(11):1492-1498.
[304]Siwik DA, Chang DL, Colucci WS. Interleukin-1β and tumor necrosis factor-a decrease collagen synthesis and increase matrix metalloproteinase activity in cardiac fibroblasts in vitro [J]. Circ Res,2000,86(12):1259-1265.
[305]Pevni D, Frolkis I, Shapira I, Schwartz D, Schwartz I, Chernichovski T, Nesher N, et al. Cardioplegic ischemia or reperfusion:which is a main trigger for tumor necrosis factor production? [J]. Int J Cardiol,2008,127(2):186-191.
[306]Moro C, Jouan MG, Rakotovao A, Toufektsian MC, Ormezzano O, Nagy N, Tosaki A, et al. Delayed expression of cytokines after reperfused myocardial infarction:possible trigger for cardiac dysfunction and ventricular remodeling [J]. Am J Physiol Heart Circ Physiol,2007,293(5):H3014-H3019.
[307]Deuchar GA, Opie LH, Lecour S. TNFa is required to confer protection in an in vivo model of classical ischaemic preconditioning [J]. Life Sci,2007, 80(18):1686-1691.
[308]Katare RG, Ando M, Kakinuma Y, Arikawa M, Yamasaki F, Sato T. Differential regulation of TNF receptors by vagal nerve stimulation protects heart against acute ischemic injury [J]. J Mol Cell Cardiol,2010,49(2):234-244.
[309]Gao Q, Zhang SZ, Cao CM, Bruce IC, Xia Q. The mitochondrial permeability transition pore and the Ca2+-activated K+channel contribute to the cardioprotection conferred by tumor necrosis factor-a [J]. Cytokine,2005,32(5):199-205.
[310]Kadokami T, McTiernan CF, Kubota T, Frye CS, Feldman AM. Sex-related survival differences in murine cardiomyopathy are associated with differences in TNF-receptor expression [J]. J Clin Invest,2000,106(4):589-597.
[311]Micheau O, Tschopp J. Induction of TNF receptor Ⅰ-mediated apoptosis via two sequential signaling complexes [J]. Cell,2003,114(2):181-190.
[312]Scheidereit C. IκB kinase complexes:gateways to NF-κB activation and transcription [J]. Oncogene,2006,25(51):6685-6705.
[313]Kleinbongard P, Schulz R, Heusch G. TNFa in myocardial ischemia/reperfusion, remodeling and heart failure [J]. Heart Fail Rev,2011,16(1):49-69.
[314]Dawn B, Guo Y, Rezazadeh A, Wang OL, Stein AB, Hunt G, Varma J, et al. Tumor necrosis factor-a does not modulate ischemia/reperfusion injury in naive myocardium but is essential for the development of late preconditioning [J]. J Mol Cell Cardiol,2004,37(1):51-61.
[315]Flaherty MP, Guo Y, Tiwari S, Rezazadeh A, Hunt G, Sanganalmath SK, Tang XL et al. The role of TNF-a receptors p55 and p75 in acute myocardial ischemia/reperfusion injury and late preconditioning [J]. J Mol Cell Cardiol,2008, 45(6):735-741.
[316]Takahashi M. High-mobility group box 1 protein (HMGB1) in ischaemic heart disease:beneficial or deleterious? [J]. Cardiovasc Res,2008,80(1):5-6.
[317]Goldstein RS, Gallowitsch-Puerta M, Yang L, Rosas-Ballina M, Huston JM, Czura CJ, Lee DC, et al. Elevated high-mobility group box 1 levels in patients with cerebral and myocardial ischemia [J]. Shock,2006,25(6):571-574.
[318]Tsung A, Sahai R, Tanaka H, Nakao A, Fink MP, Lotze MT, Yang H, et al. The nuclear factor HMGB1 mediates hepatic injury after murine liver ischemia-reperfusion [J]. J Exp Med,2005,201(7):1135-1143.
[319]Hu X, Zhou X, He B, Xu C, Wu L, Cui B, Wen H, et al. Minocycline protects against myocardial ischemia and reperfusion injury by inhibiting high mobility group box 1 protein in rats [J]. Eur J Pharmacol,2010,638(1-3):84-89.
[320]Abarbanell AM, Hartley JA, Herrmann JL, Weil BR, Wang Y, Manukyan MC, Poynter JA, et al. Exogenous high-mobility group box 1 improves myocardial recovery after acute global ischemia/reperfusion injury [J]. Surgery,2011, 149(3):329-335.
[321]Fukushima S, Coppen SR, Varela-Carver A, Yamahara K, Sarathchandra P, Smolenski RT, Yacoub MH, et al. A novel strategy for myocardial protection by combined antibody therapy inhibiting both P-selectin and intercellular adhesion molecule-1 via retrograde intracoronary route [J]. Circulation,2006,114(1 Suppl):I251-1256.
[322]Jones SP, Trocha SD, Strange MB, Granger DN, Kevil CG, Bullard DC, Lefer DJ. Leukocyte and endothelial cell adhesion molecules in a chronic murine model of myocardial reperfusion injury [J]. Am J Physiol Heart Circ Physiol,2000, 279(5):H2196-H2201.
[323]Palazzo AJ, Jones SP, Girod WG, Anderson DC, Granger DN, Lefer DJ. Myocardial ischemia-reperfusion injury in CD 18- and ICAM-1-deficient mice [J]. Am J Physiol,1998,275(6 Pt 2):H2300-H2307.
[324]Zitta K, Brandt B, Wuensch A, Meybohm P, Bein B, Steinfath M, Scholz J, et al. Interleukin-1β regulates cell proliferation and activity of extracellular matrix remodelling enzymes in cultured primary pig heart cells [J]. Biochem Biophys Res Commun,2010,399(4):542-547.
[325]Meybohm P, Gruenewald M, Albrecht M, Zacharowski KD, Lucius R, Zitta K, Koch A, et al. Hypothermia and postconditioning after cardiopulmonary resuscitation reduce cardiac dysfunction by modulating inflammation, apoptosis and remodeling [J]. PLoS One,2009,4(10):e7588.
[326]Matsushita K, Iwanaga S, Oda T, Kimura K, Shimada M, Sano M, Umezawa A, et al. Interleukin-6/soluble interleukin-6 receptor complex reduces infarct size via inhibiting myocardial apoptosis [J]. Lab Invest,2005,85(10):1210-1223.
[327]Frangogiannis NG, Mendoza LH, Lindsey ML, Ballantyne CM, Michael LH, Smith LH, Smith CW, Entman ML. IL-10 is induced in the reperfused myocardium and may modulate the reaction to injury [J]. J Immunol,2000,165(5):2798-2808.
[328]Tedgui A, Mallat Z. Anti-inflammatory mechanisms in the vascular wall [J]. Circ Res,2001,88(9):877-887.
[329]Hayward R, Nossuli TO, Scalia R, Lefer AM. Cardioprotective effect of interleukin-10 in murine myocardial ischemia-reperfusion [J]. Eur J Pharmacol, 1997,334(2-3):157-163.
[330]Dominguez-Rodriguez A, Abreu-Gonzalez P, de la Rosa A, Vargas M, Ferrer J, Garcia M. Role of endogenous interleukin-10 production and lipid peroxidation in patients with acute myocardial infarction treated with primary percutaneous transluminal coronary angioplasty, interleukin-10 and primary angioplasty [J]. Int J Cardiol,2005,99(1):77-81.
[331]Giomarelli P, Scolletta S, Borrelli E, Biagioli. Myocardial and lung injury after cardiopulmonary bypass:role of interleukin (IL)-10 [J]. Ann Thorac Surg,2003, 76(1):117-123.
[332]Dominguez RA, Abreu GP, Garcia GM, Ferrer HJ. Association between serum interleukin 10 level and development of heart failure in acute myocardial infarction patients treated by primary angioplasty [J]. Rev Esp Cardiol,2005,58(6):626-630.
[333]Zymek P, Nah DY, Bujak M, Ren G, Koerting A, Leucker T, Huebener P, et al. Interleukin-10 is not a critical regulator of infarct healing and left ventricular remodeling [J].2007,74(2):313-322.
[334]Friedman BH, Thayer JF. Anxiety and autonomic flexibility:a cardiovascular approach [J]. Biol Psychol,1998,49(3):303-323.
[335]Thayer JF, Lane RD. A model of neurovisceral integration in emotion regulation and dysregulation [J]. J Affect Disord,2000,61(3):201-216.
[336]Thayer JF, Lane RD. The role of vagal function in the risk for cardiovascular disease and mortality [J]. Biol Psychol,2007,74(2):224-242.
[337]Zamotrinsky AV, Kondratiev B, de Jong JW. Vagal neuro stimulation in patients with coronary artery disease [J]. Auton Neurosci,2001,88(1-2):109-116.
[338]Uijtdehaage SH, Thayer JF. Accentuated antagonism in the control of human heart rate [J]. Clin Auton Res,2000,10(3):107-110.
[339]Habib G. Reappraisal of the importance of heart rate as a risk factor for cardiovascular morbidity and mortality [J]. Clin Ther,1997,19 Suppl A:39-52.
[340][No authors listed] Heart rate variability:standards of measurement, physiological interpretation and clinical use. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology [J]. Circulation, 1996,93(5):1043-1065.
[341]Kiecolt-Glaser JK, McGuire L, Robles TF, Glaser R. Emotions, morbidity, and mortality:new perspectives from psychoneuroimmunology [J]. Annu Rev Psychol, 2002,53:83-107.
[342]Ershler WB, Keller ET. Age-associated increased interleukin-6 gene expression, late-life diseases, and frailty [J]. Annu Rev Med,2000,51:245-270.
[343]Blalock JE. The immune system as the sixth sense [J]. J Intern Med,2005, 257(2):126-138.
[344]Watkins LR, Maier SF. Implications of immune-to-brain communication for sickness and pain [J]. Proc Natl Acad Sci U S A,1999,96(14):7710-7713.
[345]Hansen MK, Nguyen KT, Goehler LE, Gaykema RP, Fleshner M, Maier SF, Watkins LR. Effects of vagotomy on lipopolysaccharide-induced brain interleukin-1β protein in rats [J]. Auton Neurosci,2000,85(1-3):119-126.
[346]Bernik TR, Friedman SG, Ochani M, Diraimo R, Uloa L, Yang H, Sudan S, et al. Pharmacological stimulation of the cholinergic antiinflammatory pathway [J]. J Exp Med,2002,195(6):781-788.
[347]Laye S, Parnet P, Goujon E, Dantzer R. Peripheral administration of lipopolysaccharide induces the expression of cytokine transcripts in the brain and pituitary of mice [J]. Brain Res Mol Brain Res,1994,27(1):157-162.
[348]Hosoi T, Okuma Y, Nomura Y. Electrical stimulation of afferent vagus nerve induces IL-1β expression in the brain and activates HPA axis [J]. Am J Physiol Regul Integr Comp Physiol,2000,279(1):R141-R147.
[349]Tracey KJ, Beutler B, Lowry SF, Merryweather J, Wolpe S, Milsark IW, Hariri RJ, et al. Shock and tissue injury induced by recombinant human cachectin [J]. Science, 1986,234(4775):470-474.
[350]Wang H, Bloom O, Zhang M, Vishnubhakat JM, Ombrellino M, Che J, Frazier A, et al. HMG-1 as a late mediator of endotoxin lethality in mice [J]. Science,1999, 285(5425):248-251.
[351]Dinarello CA. The interleukin-1 family:10 years of discovery [J]. FASEB J,1994, 8(15):1314-1325.
[352]Nathan CF. Secretory products of macrophages [J]. J Clin Invest,1987, 79(2):319-326.
[353]Kumins NH, Hunt J, Gamelli RL, Filkins JP. Partial hepatectomy reduces the endotoxin-induced peak circulating level of tumor necrosis factor in rats [J]. Shock, 1996,5(5):385-388.
[354]Gregory SH, Wing EJ. Neutrophil-Kupffer-cell interaction in host defenses to systemic infections [J]. Immunol Today,1998,19(11):507-510.
[355]van Westerloo DJ, Giebelen IA, Meijers JC, Daalhuisen J, de Vos AF, Levi M, van der Poll T. Vagus nerve stimulation inhibits activation of coagulation and fibrinolysis during endotoxemia in rats [J]. J Thromb Haemost,2006, 4(9):1997-2002.
[356]Wang H, Yu M, Ochani M, Amella CA, Tanovic M, Susarla S, Li JH, et al. Nicotinic acetylcholine receptor α 7 subunit is an essential regulator of inflammation [J]. Nature,2003,421(6921):384-388.
[357]Das UN. Can vagus nerve stimulation halt or ameliorate rheumatoid arthritis and lupus? [J]. Lipids Health Dis,2011,10:19.
[358]Bruchfeld A, Goldstein RS, Chavan S, Patel NB, Rosas-Ballina M, Kohn N, Qureshi AR, et al. Whole blood cytokine attenuation by cholinergic agonists ex vivo and relationship to vagus nerve activity in rheumatoid arthritis [J]. J Intern Med,2010,268(1):94-101.
[359]Taylor CT, Keely SJ. The autonomic nervous system and inflammatory bowel disease [J]. Auton Neurosci,2007,133(1):104-114.
[360]Singh V, Devgan L, Bhat S, Milner SM. The pathogenesis of burn wound conversion [J]. Ann Plast Surg,2007,59(1):109-115.
[361]Song XM, Li JG, Wang YL, Liang H, Huang Y, Yuan X, Zhou Q, et al. Effect of vagus nerve stimulation on thermal injury in rats [J]. Burns,2010,36(1):75-81.
[362]Maass DL, White J, Horton JW. IL-1β and IL-6 act synergistically with TNF-a to alter cardiac contractile function after burn trauma [J]. Shock,2002,18(4):360-366.
[363]Niederbichler AD, Papst S, Claassen L, Jokuszies A, Steinstraesser L, Hirsch T, Altintas MA, et al. Burn-induced organ dysfunction:vagus nerve stimulation attenuates organ and serum cytokine levels [J]. Burns,2009,35(6):783-789.
[364]Kumar V, Sharma A. Is neuroimmunomodulation a future therapeutic approach for sepsis? [J]. Int Immunopharmacol,2010,10(1):9-17.
[365]van Westerloo DJ, Giebelen IA, Florquin S, Daalhuisen J, Bruno MJ, de Vos AF, Tracey KJ, et al. The cholinergic anti-inflammatory pathway regulates the host response during septic peritonitis [J]. J Infect Dis,2005,191(12):2138-2148.
[366]Boland C, Collet V, Laterre E, Lecuivre C, Wittebole X, Laterre PF. Electrical vagus nerve stimulation and nicotine effects in peritonitis-induced acute lung injury in rats [J]. Inflammation,2011,34(1):29-35.
[367]Song XM, Li JG, Wang YL, Hu ZF, Zhou Q, Du ZH, Jia BH. The protective effect of the cholinergic anti-inflammatory pathway against septic shock in rats [J]. Shock, 2008,30(4):468-472.
[368]Huston JM, Gallowitsch-Puerta M, Ochani M, Ochani K, Yuan R, Rosas-Ballina M, Ashok M, et al. Transcutaneous vagus nerve stimulation reduces serum high mobility group box 1 levels and improves survival in murine sepsis [J]. Crit Care Med,2007,35(12):2762-2768.
[369]Lubbers T, Buurman W, Luyer M. Controlling postoperative ileus by vagal activation [J]. World J Gastroenterol,2010,16(14):1683-1687.
[370]Lubbers T, Luyer MD, de Haan JJ, Hadfoune M, Buurman WA, Greve JW. Lipid-rich enteral nutrition reduces postoperative ileus in rats via activation of cholecystokinin-receptors [J]. Ann Surg,2009,249(3):481-487.
[371]de Jonge WJ, The FO, van der Coelen D, Bennink RJ, Reitsma PH, van Deventer SJ, van den Wijingaard RM, et al. Mast cell degranulation during abdominal surgery initiates postoperative ileus in mice [J]. Gastroenterology,2004, 127(2):535-545.
[372]The FO, Bennink RJ, Ankum WM, Buist MR, Busch OR, Gouma DJ, van der Heide S, et al. Intestinal handling-induced mast cell activation and inflammation in human postoperative ileus [J]. Gut,2008,57(1):33-40.
[373]Kalff JC, Schraut WH, Billiar TR, Simmons RL, Bauer AJ. Role of inducible nitric oxide synthase in postoperative intestinal smooth muscle dysfunction in rodents [J]. Gastroenterology,2000,118(2):316-327.
[374]Schwarz NT, Kalff JC, Turler A, Engel BM, Watkins SC, Billiar TR, Bauer AJ. Prostanoid production via COX-2 as a causative mechanism of rodent postoperative ileus [J]. Gastroenterology,2001,121(6):1354-1371.
[375]The FO, Boeckxstaens GE, Snoek SA, Cash JL, Bennink R, Larosa GJ, van den Wijingaard RM, et al. Activation of the cholinergic anti-inflammatory pathway ameliorates postoperative ileus in mice [J]. Gastroenterology,2007, 133(4):1219-1228.
[376]De Herdt V, Bogaert S, Bracke KR, Raedt R, De Vos M, Vonck K, Boon P. Effects of vagus nerve stimulation on pro-and anti-inflammatory cytokine induction in patients with refractory epilepsy [J]. J Neuroimmunol,2009,214(1-2):104-108.
[377]Guarini S, Altavilla D, Cainazzo MM, Giuliani D, Bigiani A, Marini H, Squadrito G, et al. Efferent vagal fibre stimulation blunts nuclear factor-κB activation and protects against hypovolemic hemorrhagic shock [J]. Circulation,2003, 107(8):1189-1194.
[378]Altavilla D, Saitta A, Guarini S, Galeano M, Squadrito G, Cucinotta D, Santamaria LB, et al. Oxidative stress causes nuclear factor-κB activation in acute hypovolemic hemorrhagic shock [J]. Free Radic Biol Med,2001,30(10):1055-1066.
[379]Shahani R, Marshall JG, Rubin BB, Li RK, Walker PM, Lindsy TF. Role of TNF-a in myocardial dysfunction after hemorrhagic shock and lower-torso ischemia [J]. Am J Physiol Heart Circ Physiol,2000,278(3):H942-H950.
[380]Li W, Olshansky B. Inflammatory cytokines and nitric oxide in heart failure and potential modulation by vagus nerve stimulation [J]. Heart Fail Rev,2011, 16(2):137-145.
[381]Yellon DM, Baxter GF. Protecting the ischaemic and reperfused myocardium in acute myocardial infarction:distant dream or near reality? [J]. Heart,2000, 83(4):381-387.
[382]Piper HM, Abdallah Y, Schafer C. The first minutes of reperfusion:a window of opportunity for cardioprotection [J]. Cardiovasc Res,2004,61(3):365-371.
[383]Ezekowitz JA, Kaul P, Bakal JA, Armstrong PW, Welsh RC, Mcalister FA. Declining in-hospital mortality and increasing heart failure incidence in elderly patients with first myocardial infarction [J]. J Am Coll Cardiol,2009,53(1):13-20.
[384]Shanmuganathan S, Hausenloy DJ, Duchen MR, Yellon DM. Mitochondrial permeability transition pore as a target for cardioprotection in the human heart [J]. Am J Physiol Heart Circ Physiol,2005,289(1):H237-H242.
[385]Loffelholz K, Pappano AJ. The parasympathetic neuroeffector junction of the heart [J]. Pharmacol Rev,1985,37(1):1-24.
[386]Rardon DP, Bailey JC. Parasympathetic effects on electrophysiologic properties of cardiac ventricular tissue [J]. J Am Coll Cardiol,1983,2(6):1200-1209.
[387]Amlie JP, Refsum H. Vagus-induced changes in ventricular electrophysiology of the dog heart with and without β-blockade [J]. J Cardiovasc Pharmacol,1981, 3(6):1203-1210.
[388]Kawada T, Yamazaki T, Akiyama T, Li M, Ariumi H, Mori H, Sunagawa K, et al. Vagal stimulation suppresses ischemia-induced myocardial interstitial norepinephrine release [J]. Life Sci,2006,78(8):882-887.
[389]Schomig A, Fischer S, Kurz T, Richardt G, Schomig E. Nonexocytotic release of endogenous noradrenaline in the ischemic and anoxic rat heart:mechanism and metabolic requirements [J]. Circ Res,1987,60(2):194-205.
[390]Bazzani C, Guarini S, Botticelli AR, Zaffe D, Tomasi A, Bini A, Cainazzo MM, et al. Protective effect of melanocortin peptides in rat myocardial ischemia [J]. J Pharmacol Exp Ther,2001,297(3):1082-1087.
[391]O'Neill CA, Fu L W, Halliwell B, Longhurst JC. Hydroxyl radical production during myocardial ischemia and reperfusion in cats [J]. Am J Physiol,1996,271(2 Pt 2):H660-H667.
[392]Bolli R, Marban E. Molecular and cellular mechanisms of myocardial stunning [J]. Physiol Rev,1999,79(2):609-634.
[393]Ramasamy R, Hwang YC, Liu Y, Son NH, Ma N, Parkinson J, Sciaccca R, et al. Metabolic and functional protection by selective inhibition of nitric oxide synthase 2 during ischemia-reperfusion in isolated perfused hearts [J]. Circulation,2004, 109(13):1668-1673.
[394]Mioni C, Giuliani D, Cainazzo MM, Leone S, Bazzani C, Grieco P, Novellino E, et al. Further evidence that melanocortins prevent myocardial reperfusion injury by activating melanocortin MC3 receptors [J]. Eur J Pharmacol,2003,477(3):227-234.
[395]Rardon DP, Bailey JC. Direct effects of cholinergic stimulation on ventricular automaticity in guinea pig myocardium [J]. Circ Res,1983,52(1):105-110.
[396]Hashimoto K, Moe GK. Transient depolarizations induced by acetylstrophanthidin in specialized tissue of dog atrium and ventricle [J]. Circ Res,1973,32(5):618-624.
[397]Sammel NL, Norris RM, Hughes CF, Johnson RN, Ashton NG, Elliott RL. Severity of canine myocardial infarcts in relation to indices of oxygen demand: preservation of myocardial creatine kinase activity by vagal stimulation and propranolol [J]. Cardiovasc Res,1983,17(1):50-60.
[398]Shinke T, Takeuchi M, Takaoka H, Yokoyama M. Beneficial effects of heart rate reduction on cardiac mechanics and energetics in patients with left ventricular dysfunction [J]. Jpn Circ J,1999,63(12):957-964.
[399]Maughan WL, Sunagawa K, Burkhoff D, Graves WL Jr, Hunter WC, Sagawa K. Effect of heart rate on the canine end-systolic pressure-volume relationship [J]. Circulation,1985,72(3):654-659.
[400]Buck JD, Warltier DC, Hardman HF, Gross GJ. Effects of sotalol and vagal stimulation on ischemic myocardial blood flow distribution in the canine heart [J]. J Pharmacol Exp Ther,1981,216(2):347-351.
[401]Feigl EO. Parasympathetic control of coronary blood flow in dogs [J]. Circ Res, 1969,25(5):509-519.
[402]Reid JV, Ito BR, Huang AH, Buffington CW, Feigl EO. Parasympathetic control of transmural coronary blood flow in dogs [J]. Am J Physiol,1985,249(2 Pt 2):H337-H343.
[403]Feliciano L, Henning RJ. Vagal nerve stimulation releases vasoactive intestinal peptide which significantly increases coronary artery blood flow [J]. Cardiovasc Res,1998,40(1):45-55.
[404]Henning RJ, Sawmiller DR. Vasoactive intestinal peptide:cardiovascular effects [J]. Cardiovasc Res,2001,49(1):27-37.
[405]Schachter SC. Vagus nerve stimulation therapy summary:five years after FDA approval [J]. Neurology,2002,59(6 Suppl 4):S15-S20.
[406]Uthman BM, Reichl AM, Dean JC, Eisenschenk S, Gilmore R, Reid S, Roper SN, et al. Effectiveness of vagus nerve stimulation in epilepsy patients:a 12-year observation [J]. Neurology,2004,63(6):1124-1126.
[407]Nemeroff CB, Mayberg HS, Krahl SE, Mcnamara J, Frazer A, Henry TR, George MS, et al. VNS therapy in treatment-resistant depression:clinical evidence and putative neurobiological mechanisms [J]. Neuropsychopharmacology,2006, 31(7):1345-1355.
[408]Vanoli E, De Ferrari GM, Stramba-Badiale M, Hull SS Jr, Foreman RD, Schwartz PJ. Vagal stimulation and prevention of sudden death in conscious dogs with a healed myocardial infarction [J]. Circ Res,1991,68(5):1471-1481.
[409]Li M, Zheng C, Sato T, Kawada T, Sugimachi M, Sunagawa K. Vagal nerve stimulation markedly improves long-term survival after chronic heart failure in rats [J]. Circulation,2004,109(1):120-124.
[410]Vinten-Johansen J, Zhao ZQ, Jiang R, Zatta AJ, Dobson GP. Preconditioning and postconditioning:innate cardioprotection from ischemia-reperfusion injury [J]. J Appl Physiol,2007,103(4):1441-1448.
[411]De Ferrari GM, Vanoli E, Stramba-Badiale M, Hull SS Jr, Foreman RD, Schwartz PJ. Vagal reflexes and survival during acute myocardial ischemia in conscious dogs with healed myocardial infarction [J]. Am J Physiol,1991,261(1 Pt 2):H63-H69.
[412]Vanoli E, De Ferrari GM, Stramba-Badiale M, Hull SS Jr, Foreman RD, Schwartz PJ. Vagal stimulation and prevention of sudden death in conscious dogs with a healed myocardial infarction [J]. Circ Res,1991,68(5):1471-1481.
[413]Olshansky B, Sabbah HN, Hauptman PJ, Colucci WS. Parasympathetic nervous system and heart failure:pathophysiology and potential implications for therapy [J]. Circulation,2008,118(8):863-871.
[414]Zamotrinsky A, Afanasiev S, Karpov RS, Cherniavsky A. Effects of electrostimulation of the vagus afferent endings in patients with coronary artery disease [J]. Coron Artery Dis,1997,8(8-9):551-557.
[415]Tordoir JH, Scheffers I, Schmidli J, Savolainen H, Liebeskind U, Hansky B, Herold U, et al. An implantable carotid sinus baroreflex activating system:surgical technique and short-term outcome from a multi-center feasibility trial for the treatment of resistant hypertension [J]. Eur J Vasc Endovasc Surg,2007, 33 (4):414-421.
[416]Schauerte P, Mischke K, Plisiene J, Waldmann M, Zarse M, Stellbrink C, Schimpf T, et al. Catheter stimulation of cardiac parasympathetic nerves in humans:a novel approach to the cardiac autonomic nervous system [J]. Circulation,2001, 104(20):2430-2435.
[417]Dietrich S, Smith J, Scherzinger C, Hofmann-Preiss K, Freitag T, Eisenkolb A, Ringler R. A novel transcutaneous vagus nerve stimulation leads to brainstem and cerebral activations measured by functional MRI [J]. Biomed Tech (Berl),2008, 53(3):104-111.
[418]Kraus T, Hosl K, Kiess O, Schanze A, Kornhuber J, Forster C. BOLD fMRI deactivation of limbic and temporal brain structures and mood enhancing effect by transcutaneous vagus nerve stimulation [J]. J Neural Transm,2007, 114(11):1485-1493.
[419]Ventureyra EC. Transcutaneous vagus nerve stimulation for partial onset seizure therapy. A new concept [J]. Childs Nerv Syst,2000,16(2):101-102.
[420]Boon P, D'Have M, Van Walleghem P, Michielsen G, Vonck K, Caemaert J, De Reuck J. Direct medical costs of refractory epilepsy incurred by three different treatment modalities:a prospective assessment [J]. Epilepsia,2002,43(1):96-102.
[421]Ben-Menachem E, Hellstrom K, Verstappen D. Analysis of direct hospital costs before and 18 months after treatment with vagus nerve stimulation therapy in 43 patients [J]. Neurology,2002,59(6 Suppl 4):S44-S47.
[422]Forbes RB, Macdonald S, Eljamel S, Roberts RC. Cost-utility analysis of vagus nerve stimulators for adults with medically refractory epilepsy [J]. Seizure,2003, 12(5):249-256.
[423]Forbes R. Cost-utility of vagus nerve stimulation (VNS) therapy for medically refractory epilepsy-an update [J]. Seizure,2008,17(4):387-388.
[2]Lloyd-Jones D, Adams RJ, Brown TM, Carnethon M, Dai S, De Simone G, Ferguson TB, et al. Heart disease and stroke statistics--2010 update:a report from the American Heart Association [J]. Circulation,2010,121(7):e46-e215.
[3]Liu L. Cardiovascular diseases in China [J]. Biochem Cell Biol,2007,85(2):157-163.
[4]Murray CJ, Lopez AD. Alternative projections of mortality and disability by cause 1990-2020:Global Burden of Disease Study [J]. Lancet,1997, 349(9064):1498-1504.
[5]Miller TD, Christian TF, Hopfenspirger MR, Hodge DO, Gersh BJ, Gibbons RJ. Infarct size after acute myocardial infarction measured by quantitative tomographic 99mTc sestamibi imaging predicts subsequent mortality [J]. Circulation,1995, 92(3):334-341.
[6]De Hert SG, Preckel B, Hollmann MW, Schlack WS. Drugs mediating myocardial protection [J]. Eur J Anaesthesiol,2009,26(12):985-995.
[7]Yellon DM, Hausenloy DJ. Myocardial reperfusion injury [J]. N Engl J Med,2007, 357(11):1121-1135.
[8]Willerson JT, Watson JT, Hutton I, Templeton GH, Fixler DE. Reduced myocardial reflow and increased coronary vascular resistance following prolonged myocardial ischemia in the dog [J]. Circ Res,1975,36(6):771-781.
[9]Willerson JT, Scales F, Mukherjee A, Platt M, Templeton GH, Fink GS, Buja LM. Abnormal myocardial fluid retention as an early manifestation of ischemic injury [J]. Am J Pathol,1977,87(1):159-188.
[10]Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction:a quantitative review of 23 randomised trials [J]. Lancet,2003,361(9351):13-20.
[11]Jang IS, Park MY, Shin IW, Sohn JT, Lee HK, Chung YK. Ethyl pyruvate has anti-inflammatory and delayed myocardial protective effects after regional ischemia/reperfusion injury [J]. Yonsei Med J,2010,51(6):838-844.
[12]Jin YC, Kim CW, Kim YM, Nizamutdinova IT, Ha YM, Kim JI, Seo HG, et al. Cryptotanshinone, a lipophilic compound of Salvia miltiorrriza root, inhibits TNF-a induced expression of adhesion molecules in HUVEC and attenuates rat myocardial ischemia/reperfusion injury in vivo [J]. Eur J Pharmacol,2009,614(1-3):91-97.
[13]Jennings RB, Sommers HM, Smyth GA, Flack HA, Linn H. Myocardial necrosis induced by temporary occlusion of a coronary artery in the dog [J]. Arch Pathol, 1960,70:68-78.
[14]Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia:a delay of lethal cell injury in ischemic myocardium [J]. Circulation,1986,74(5):1124-1136.
[15]Hausenloy DJ, Tsang A, Mocanu MM, Yellon DM. Ischemic preconditioning protects by activating prosurvival kinases at reperfusion [J]. Am J Physiol Heart Circ Physiol,2005,288(2):H971-H976.
[16]Cokkinos DV, Pantos C. Myocardial protection in man--from research concept to clinical practice [J]. Heart Fail Rev,2007,12(3-4):345-362.
[17]Zhao ZQ, Corvera JS, Halkos ME, Kerendi F, Wang NP, Guyton RA, Vinten-Johansen J. Inhibition of myocardial injury by ischemic postconditioning during reperfusion:comparison with ischemic preconditioning [J]. Am J Physiol Heart Circ Physiol,2003,285(2):H579-H588.
[18]Lie RH, Hasenkam JM, Nielsen TT, Poulsen R, Sloth E. Post-conditioning reduces infarct size in an open-chest porcine acute ischemia-reperfusion model [J]. Acta Anaesthesiol Scand,2008,52(9):1188-1193.
[19]Kin H, Zhao ZQ, Sun HY, Wang NP, Corvera JS, Halkos ME, Kerendi F, et al. Postconditioning attenuates myocardial ischemia-reperfusion injury by inhibiting events in the early minutes of reperfusion [J]. Cardiovasc Res,2004,62(l):74-85.
[20]Sadat U, Walsh SR, Varty K. Cardioprotection by ischemic postconditioning during surgical procedures [J]. Expert Rev Cardiovasc Ther,2008,6(7):999-1006.
[21]Downey JM, Cohen MV. Why do we still not have cardioprotective drugs? [J]. CircJ,2009,73(7):1171-1177.
[22]Kloner RA, Rezkalla SH. Cardiac protection during acute myocardial infarction: where do we stand in 2004? [J]. J Am Coll Cardiol,2004,44(2):276-286.
[23]Zhao ZQ. Postconditioning in reperfusion injury:a status report [J]. Cardiovasc Drugs Ther,2010,24(3):265-279.
[24]Tracey KJ. Reflex control of immunity [J]. Nat Rev Immunol,2009,9(6):418-428.
[25]Zitnik RJ. Treatment of chronic inflammatory diseases with implantable medical devices [J]. Ann Rheum Dis,2011,70 Suppl 1:i67-i70.
[26]Wu W, Lu Z. Loss of anti-arrhythmic effect of vagal nerve stimulation on ischemia-induced ventricular tachyarrhythmia in aged rats [J]. Tohoku J Exp Med, 2011,223(1):27-33.
[27]Lown B, Verrier RL. Neural activity and ventricular fibrillation [J]. N Engl J Med, 1976,294(21):1165-1170.
[28]Katare RG, Ando M, Kakinuma Y, Arikawa M, Handa T, Yamasaki F, Sato T. Vagal nerve stimulation prevents reperfusion injury through inhibition of opening of mitochondrial permeability transition pore independent of the bradycardiac effect [J]. J Thorac Cardiovasc Surg,2009,137(1):223-231.
[29]Mioni C, Bazzani C, Giuliani D, Altavilla D, Leone S, Ferrari A, Minutoli L, et al. Activation of an efferent cholinergic pathway produces strong protection against myocardial ischemia/reperfusion injury in rats [J]. Crit Care Med,2005, 33(11):2621-2628.
[30]Nakayama Y, Miyano H, Shishido T, Inagaki M, Kawada T, Sugimachi M, Sunagawa K. Heart rate-independent vagal effect on end-systolic elastance of the canine left ventricle under various levels of sympathetic tone [J]. Circulation,2001, 104(19):2277-2279.
[31]Ben-Menachem E. Vagus nerve stimulation, side effects, and long-term safety [J]. J Clin Neurophysiol,2001,18(5):415-418.
[32]Howland RH, Shutt LS, Berman SR, Spotts CR, Denko T. The emerging use of technology for the treatment of depression and other neuropsychiatric disorders [J]. Ann Clin Psychiatry,2011,23(1):48-62.
[33]Shuchman M. Approving the vagus-nerve stimulator for depression [J]. N Engl J Med,2007,356(16):1604-1607.
[34]De Ferrari GM, Schwartz PJ. Vagus nerve stimulation:from pre-clinical to clinical application:challenges and future directions [J]. Heart Fail Rev,2011, 16(2):195-203.
[35]Xin P, Zhu W, Li J, Ma S, Wang L, Liu M, Li J, et al. Combined local ischemic postconditioning and remote perconditioning recapitulate cardioprotective effects of local ischemic preconditioning [J]. Am J Physiol Heart Circ Physiol,2010, 298(6):H1819-H1831.
[36]Tamareille S, Mateus V, Ghaboura N, Jeanneteau J, Croue A, Henrion D, Furber A, et al. RISK and SAFE signaling pathway interactions in remote limb ischemic perconditioning in combination with local ischemic postconditioning [J]. Basic Res Cardiol,2011,106(6):1329-1339.
[37]Gonon AT, Jung C, Yang J, Sjoquist PO, Pernow J. The combination of L-arginine and ischaemic post-conditioning at the onset of reperfusion limits myocardial injury in the pig [J]. Acta Physiol (Oxf),2011,201 (2):219-226.
[38]Huang Z, Zhong X, Irwin MG, Ji S, Wong GT, Liu Y, Xia ZY, et al. Synergy of isoflurane preconditioning and propofol postconditioning reduces myocardial reperfusion injury in patients [J]. Clin Sci (Lond),2011,121(2):57-69.
[39]Menger MD, Vollmar B. Pathomechanisms of ischemia-reperfusion injury as the basis for novel preventive strategies:is it time for the introduction of pleiotropic compounds? [J]. Transplant Proc,2007,39(2):485-488.
[40]Vessey DA, Li L, Kelley M, Karliner JS. Combined sphingosine, S1P and ischemic postconditioning rescue the heart after protracted ischemia [J]. Biochem Biophys Res Commun,2008,375(3):425-429.
[41]Cantley LC. The phosphoinositide 3-kinase pathway [J]. Science,2002, 296(5573):1655-1657.
[42]Tong H, Chen W, Steenbergen C, Murphy E. Ischemic preconditioning activates phosphatidylinositol-3-kinase upstream of protein kinase C [J]. Circ Res,2000, 87(4):309-315.
[43]Uchiyama T, Engelman RM, Maulik N, Das DK. Role of Akt signaling in mitochondrial survival pathway triggered by hypoxic preconditioning [J]. Circulation,2004,109(24):3042-3049.
[44]Tsang A, Hausenloy DJ, Mocanu MM, Yellon DM. Postconditioning:a form of "modified reperfusion" protects the myocardium by activating the phosphatidylinositol 3-kinase-Akt pathway [J]. Circ Res,2004,95(3):230-232.
[45]Malik S, Sharma AK, Bharti S, Nepal S, Bhatia J, Nag TC, Narang R, et al. In vivo cardioprotection by pitavastatin from ischemic-reperfusion injury through suppression of IKK/NF-κB and upregulation of pAkt-e-NOS [J]. J Cardiovasc Pharmacol,2011,58(2):199-206.
[46]Ibacache M, Sanchez G, Pedrozo Z, Galvez F, Humeres C, Echevarria G, Duaso J, et al. Dexmedetomidine preconditioning activates pro-survival kinases and attenuates regional ischemia/reperfusion injury in rat heart [J]. Biochim Biophys Acta,2011,1822(4):537-545.
[47]Birnbaum Y, Long B, Qian J, Perez-Polo JR, Ye Y. Pioglitazone limits myocardial infarct size, activates Akt, and upregulates cPLA2 and COX-2 in a PPAR-gamma-independent manner [J]. Basic Res Cardiol,2011,106(3):431-446.
[48]Yellon DM, Downey JM. Preconditioning the myocardium:from cellular physiology to clinical cardiology [J]. Physiol Rev,2003,83(4):1113-1151.
[49]Krieg T, Qin Q, Philipp S, Alexeyev MF, Cohen MV, Downey JM. Acetylcholine and bradykinin trigger preconditioning in the heart through a pathway that includes Akt and NOS [J]. Am J Physiol Heart Circ Physiol,2004,287(6):H2606-H2611.
[50]Negoro S, Kunisada K, Tone E, Funamoto M, Oh H, Kishimoto T, Yamauchi-Takihara K. Activation of JAK/STAT pathway transduces cytoprotective signal in rat acute myocardial infarction [J]. Cardiovasc Res,2000,47(4):797-805.
[51]Otani H. Ischemic preconditioning:from molecular mechanisms to therapeutic opportunities [J]. Antioxid Redox Signal,2008,10(2):207-247.
[52]Tarnavski O. Mouse surgical models in cardiovascular research [J]. Methods Mol Biol,2009,573:115-137.
[53]Peart JN, Gross GJ. Cardioprotection following adenosine kinase inhibition in rat hearts [J]. Basic Res Cardiol,2005,100(4):328-336.
[54]Kawada T, Yamazaki T, Akiyama T, Kitagawa H, Shimizu S, Mizuno M, Li M, et al. Vagal stimulation suppresses ischemia-induced myocardial interstitial myoglobin release [J]. Life Sci,2008,83(13-14):490-495.
[55]Kloner RA, Dow J, Bhandari A. Postconditioning markedly attenuates ventricular arrhythmias after ischemia-reperfusion [J]. J Cardiovasc Pharmacol Ther,2006, 11(1):55-63.
[56]Oozawa S, Mori S, Kanke T, Takahashi H, Liu K, Tomono Y, Asanuma M, et al. Effects of HMGB1 on ischemia-reperfusion injury in the rat heart [J]. Circ J,2008, 72(7):1178-1184.
[57]Lim SY, Davidson SM, Hausenloy DJ, Yellon DM. Preconditioning and postconditioning:the essential role of the mitochondrial permeability transition pore [J]. Cardiovasc Res,2007,75(3):530-535.
[58]Groban L, Vernon JC, Butterworth J. Intrathecal morphine reduces infarct size in a rat model of ischemia-reperfusion injury [J]. Anesth Analg,2004,98(4):903-909.
[59]Turan NN, Basgut B, Aypar E, Ark M, Iskit AB, Cakici I. Chemical preconditioning effect of 3-nitropropionic acid in anesthetized rat heart [J]. Life Sci,2008, 82(17-18):928-933.
[60]Chiari PC, Bienengraeber MW, Pagel PS, Krolikowski JG, Kersten JR, Warltier DC. Isoflurane protects against myocardial infarction during early reperfusion by activation of phosphatidylinositol-3-kinase signal transduction:evidence for anesthetic-induced postconditioning in rabbits [J]. Anesthesiology,2005, 102(1):102-109.
[61]Stumpner J, Redel A, Kellermann A, Lotz CA, Blomeyer CA, Smul TM, Kehl F, et al. Differential role of Pim-1 kinase in anesthetic-induced and ischemic preconditioning against myocardial infarction [J]. Anesthesiology,2009, 111(6):1257-1264.
[62]Peoples GE, McLennan PL, Howe PR, Groeller H. Fish oil reduces heart rate and oxygen consumption during exercise [J]. J Cardiovasc Pharmacol,2008, 52(6):540-547.
[63]Pourkhalili K, Hajizadeh S, Tiraihi T, Akbari Z, Esmailidehaj M, Bigdeli MR, Khoshbaten A. Ischemia and reperfusion-induced arrhythmias:role of hyperoxic preconditioning [J]. J Cardiovasc Med (Hagerstown),2009,10(8):635-642.
[64]Ferrera R, Benhabbouche S, Bopassa JC, Li B, Ovize M. One hour reperfusion is enough to assess function and infarct size with TTC staining in Langendorff rat model [J]. Cardiovasc Drugs Ther,2009,23(4):327-331.
[65]刘万里,薛茜,曹明芹,马金风.用SPSS实现完全随机设计多组比较秩和检验的多重比较[J].地方病通报,2007,22(2)：27-29.
[66]颜虹,徐勇勇,赵耐青.医学统计学[M].北京：人民卫生出版社,2005：269.
[67]Guerra MS, Roncon-Albuquerque RJ, Lourenco AP, Falcao-Pires I, Cibrao-Coutinho P, Leite-Moreira AF. Remote myocardium gene expression after 30 and 120 min of ischaemia in the rat [J]. Exp Physiol,2006,91(2):473-480.
[68]Wysoczynski M, Shin DM, Kucia M, Ratajczak MZ. Selective upregulation of interleukin-8 by human rhabdomyosarcomas in response to hypoxia:therapeutic implications [J]. Int J Cancer,2010,126(2):371-381.
[69]Weman SM, Karhunen PJ, Penttila A, Jarvinen AA, Salminen US. Reperfusion injury associated with one-fourth of deaths after coronary artery bypass grafting [J]. Ann Thorac Surg,2000,70(3):807-812.
[70]Moore GW, Hutchins GM. Coronary artery bypass grafts in 109 autopsied patients. Statistical analysis of graft and anastomosis patency and regional myocardial injury [J]. JAMA,1981,246(16):1785-1789.
[71]Bulkely BH, Hutchins GM. Myocardial consequences of coronary artery bypass graft surgery. The paradox of necrosis in areas of revascularization [J]. Circulation, 1977,56(6):906-913.
[72]Diaz RJ, Wilson GJ. Studying ischemic preconditioning in isolated cardiomyocyte models [J]. Cardiovasc Res,2006,70(2):286-296.
[73]Hausenloy DJ, Yellon DM. Preconditioning and postconditioning:underlying mechanisms and clinical application [J]. Atherosclerosis,2009,204(2):334-341.
[74]Kin H, Zhao ZQ, Sun HY, Wang NP, Corvera JS, Halkos ME, Kerendi F, et al. Postconditioning attenuates myocardial ischemia-reperfusion injury by inhibiting events in the early minutes of reperfusion [J]. Cardiovasc Res,2004,62(1):74-85.
[75]Kilgore KS, Friedrichs GS, Homeister JW, Lucchesi BR. The complement system in myocardial ischaemia/reperfusion injury [J]. Cardiovasc Res,1994,28(4):437-444.
[76]Frangogiannis NG, Smith CW, Entman ML. The inflammatory response in myocardial infarction [J]. Cardiovasc Res,2002,53(1):31-47.
[77]Jolly SR, Kane WJ, Hook BG, Abrams GD, Kunkel SL, Lucchesi BR. Reduction of myocardial infarct size by neutrophil depletion:effect of duration of occlusion [J]. Am Heart J,1986,112(4):682-690.
[78]Entman ML, Smith CW. Postreperfusion inflammation:a model for reaction to injury in cardiovascular disease [J]. Cardiovasc Res,1994,28(9):1301-1311.
[79]Crawford MH, Grover FL, Kolb WP, Mcmahan CA, Orourke RA, Mcmanus LM, Pinckard RN. Complement and neutrophil activation in the pathogenesis of ischemic myocardial injury [J]. Circulation,1988,78(6):1449-1458.
[80]Gao XM, Liu Y, White D, Su Y, Drew BG, Bruce CR, Kiriazis H, et al. Deletion of macrophage migration inhibitory factor protects the heart from severe ischemia-reperfusion injury:a predominant role of anti-inflammation [J]. J Mol Cell Cardiol,2011,50(6):991-999.
[81]Birdsall HH, Green DM, Trial J, Youker KA, Burns AR, Mackay CR, Larosa GJ, et al. Complement C5a, TGF-β1, and MCP-1, in sequence, induce migration of monocytes into ischemic canine myocardium within the first one to five hours after reperfusion [J]. Circulation,1997,95(3):684-692.
[82]Dhalla NS, Elmoselhi AB, Hata T, Makino N. Status of myocardial antioxidants in ischemia-reperfusion injury [J]. Cardiovasc Res,2000,47(3):446-456.
[83]Velasco CE, Turner M, Inagami T, Atkinson JB, Virmani R, Jackson EK, Murray JJ, et al. Reperfusion enhances the local release of endothelin after regional myocardial ischemia [J]. Am Heart J,1994,128(3):441-451.
[84]Engler RL, Dahlgren MD, Morris DD, Peterson MA, Schmid-Schonbein GW. Role of leukocytes in response to acute myocardial ischemia and reflow in dogs [J]. Am J Physiol,1986,251(2 Pt 2):H314-H323.
[85]Montecucco F, Lenglet S, Braunersreuther V, Pelli G, Pellieux C, Montessuit C, Lerch R, et al. Single administration of the CXC chemokine-binding protein Evasin-3 during ischemia prevents myocardial reperfusion injury in mice [J]. Arterioscler Thromb Vasc Biol,2010,30(7):1371-1377.
[86]Babior BM. The respiratory burst of phagocytes [J]. J Clin Invest,1984, 73(3):599-601.
[87]Schulz R, Aker S, Belosjorow S, Heusch G. TNFa in ischemia/reperfusion injury and heart failure [J]. Basic Res Cardiol,2004,99(1):8-11.
[88]Friedrichs GS, Swillo RE, Jow B, Bridal T, Numann R, Warner LM, Killar LM, et al. Sphingosine modulates myocyte electrophysiology, induces negative inotropy, and decreases survival after myocardial ischemia [J]. J Cardiovasc Pharmacol,2002, 39(1):18-28.
[89]Skyschally A, Gres P, van Caster P, van de Sand A, Boengler K, Schulz R, Heusch G. Reduced calcium responsiveness characterizes contractile dysfunction following coronary microembolization [J]. Basic Res Cardiol,2008,103(6):552-559.
[90]Kimura H, Shintani-Ishida K, Nakajima M, Liu S, Matsumoto K, Yoshida K. Ischemic preconditioning or p38 MAP kinase inhibition attenuates myocardial TNF a production and mitochondria damage in brief myocardial ischemia [J]. Life Sci, 2006,78(17):1901-1910.
[91]Sun M, Dawood F, Wen WH, Chen M, Dixon I, Kirshenbaum LA, Liu PP. Excessive tumor necrosis factor activation after infarction contributes to susceptibility of myocardial rupture and left ventricular dysfunction [J]. Circulation, 2004,110(20):3221-3228.
[92]Hayashidani S, Tsutsui H, Ikeuchi M, Shiomi T, Matsusaka H, Kubota T, Imanaka-Yoshida K, et al. Targeted deletion of MMP-2 attenuates early LV rupture and late remodeling after experimental myocardial infarction [J]. Am J Physiol Heart Circ Physiol,2003,285(3):H1229-H1235.
[93]Hu X, Cui B, Zhou X, Xu C, Lu Z, Jiang H. Ethyl pyruvate reduces myocardial ischemia and reperfusion injury by inhibiting high mobility group box 1 protein in rats [J]. Mol Biol Rep,2012,39(1):227-231.
[94]Andersson U, Wang H, Palmblad K, Aveberger AC, Bloom O, Erlandsson-Harris H, Janson A, et al. High mobility group 1 protein (HMG-1) stimulates proinflammatory cytokine synthesis in human monocytes [J]. J Exp Med,2000,192(4):565-570.
[95]Entman ML, Youker K, Shappell SB, Siegel C, Rothlein R, Dreyer WJ, Schmalstieg FC, et al. Neutrophil adherence to isolated adult canine myocytes. Evidence for a CD18-dependent mechanism [J]. J Clin Invest,1990,85(5):1497-1506.
[96]Smith CW, Entman ML, Lane CL, Beaudet AL, Ty Ti, Youker K, Hawkins HK, et al. Adherence of neutrophils to canine cardiac myocytes in vitro is dependent on intercellular adhesion molecule-1 [J]. J Clin Invest,1991,88(4):1216-1223.
[97]Bujak M, Frangogiannis NG. The role of IL-1 in the pathogenesis of heart disease [J]. Arch Immunol Ther Exp (Warsz),2009,57(3):165-176.
[98]Suzuki K, Murtuza B, Smolenski RT, Sammut IA, Suzuki N, Kaneda Y, Yacoub MH. Overexpression of interleukin-1 receptor antagonist provides cardioprotection against ischemia-reperfusion injury associated with reduction in apoptosis [J]. Circulation,2001,104(12 Suppl 1):I303-I308.
[99]Smart N, Mojet MH, Latchman DS, Marber MS, Duchen MR, Heads RJ. IL-6 induces PI 3-kinase and nitric oxide-dependent protection and preserves mitochondrial function in cardiomyocytes [J]. Cardiovasc Res,2006,69(1):164-177.
[100]Andersson J. The inflammatory reflex—introduction [J]. J Intern Med,2005, 257(2):122-125.
[101]Johnston GR, Webster NR. Cytokines and the immunomodulatory function of the vagus nerve [J]. Br J Anaesth,2009,102(4):453-462.
[102]Borovikova LV, Ivanova S, Zhang M, Yang H, Botchkina GI, Watkins LR, Wang H, et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin [J]. Nature,2000,405(6785):458-462.
[103]Zhou Y, Zuo X, Li Y, Wang Y, Zhao H, Xiao X. Nicotine inhibits tumor necrosis factor-a induced IL-6 and IL-8 secretion in fibroblast-like synoviocytes from patients with rheumatoid arthritis [J]. Rheumatol Int,2012,32(1):97-104.
[104]Meregnani J, Clarencon D, Vivier M, Peinnequin A, Mouret C, Snniger V, Picq C, et al. Anti-inflammatory effect of vagus nerve stimulation in a rat model of inflammatory bowel disease [J]. Auton Neurosci,2011,160(1-2):82-89.
[105]Bernik TR, Friedman SG, Ochani M, Diraimo R, Susarla S, Czura CJ, Tracey KJ. Cholinergic antiinflammatory pathway inhibition of tumor necrosis factor during ischemia reperfusion [J]. J Vasc Surg,2002,36(6):1231-1236.
[106]Uemura K, Zheng C, Li M, Kawada T, Sugimachi M. Early short-term vagal nerve stimulation attenuates cardiac remodeling after reperfused myocardial infarction [J]. J Card Fail,2010,16(8):689-699.
[107]Bolognese L, Cerisano G. Early predictors of left ventricular remodeling after acute myocardial infarction [J]. Am Heart J,1999,138(2 Pt 2):S79-S83.
[108]Hearse DJ. Reperfusion of the ischemic myocardium [J]. J Mol Cell Cardiol,1977, 9(8):605-616.
[109]Cramer JA, Fisher R, Ben-Menachem E, French J, Mattson RH. New antiepileptic drugs:comparison of key clinical trials [J]. Epilepsia,1999,40(5):590-600.
[110]The Vagus Nerve Stimulation Study Group. A randomized controlled trial of chronic vagus nerve stimulation for treatment of medically intractable seizures [J]. Neurology,1995,45(2):224-230.
[111]Ben-Menachem E, Hellstrom K, Waldton C, Augustinsson LE. Evaluation of refractory epilepsy treated with vagus nerve stimulation for up to 5 years [J]. Neurology,1999,52(6):1265-1267.
[112]DeGiorgio CM, Schachter SC, Handforth A, Salinsky M, Thompson J, Uthman B, Reed R, et al. Prospective long-term study of vagus nerve stimulation for the treatment of refractory seizures [J]. Epilepsia,2000,41(9):1195-1200.
[113]Morris GR, Mueller WM. Long-term treatment with vagus nerve stimulation in patients with refractory epilepsy. The Vagus Nerve Stimulation Study Group E01-E05 [J]. Neurology,1999,53(8):1731-1735.
[114]Andreka G, Vertesaljai M, Szantho G, Font G, Piroth Z, Fontos G, Juhasz ED, et al. Remote ischaemic postconditioning protects the heart during acute myocardial infarction in pigs [J]. Heart,2007,93(6):749-752.
[115]Bφtker HE, Kharbanda R, Schmidt MR, Bφttcher M, Kaltoft AK, Terkelsen CJ, Munk K, et al. Remote ischaemic conditioning before hospital admission, as a complement to angioplasty, and effect on myocardial salvage in patients with acute myocardial infarction:a randomised trial [J]. Lancet,2010,375(9716):727-734.
[116]Gritsopoulos G, Iliodromitis EK, Zoga A, Farmakis D, Demerouti E, Papalois A, Paraskevaidis IA, et al. Remote postconditioning is more potent than classic postconditioning in reducing the infarct size in anesthetized rabbits [J]. Cardiovasc Drugs Ther,2009,23(3):193-198.
[117]Schmidt MR, Smerup M, Konstantinov IE, Shimizu M, Li J, Cheung M, White PA, et al. Intermittent peripheral tissue ischemia during coronary ischemia reduces myocardial infarction through a KATP-dependent mechanism:first demonstration of remote ischemic preconditioning [J]. Am J Physiol Heart Circ Physiol,2007, 292(4):H1883-H1890.
[118]Hu X, Jiang H, Ma F, Xu C, Bo C, Wen H, Wu B, et al. Similarities between ischemic preconditioning and postconditioning in myocardial ischemia/reperfusion injury [J]. Int J Cardiol,2010,144(1):135-136.
[119]Manintveld OC, Hekkert ML, van der Ploeg NT, Verdouw PD, Duncker DJ. Interaction between pre- and postconditioning in the in vivo rat heart [J]. Exp Biol Med (Maywood),2009,234(11):1345-1354.
[120]Patten RD, Hall-Porter MR. Small animal models of heart failure:development of novel therapies, past and present [J]. Circ Heart Fail,2009,2(2):138-144.
[121]Wu YN, Yu H, Zhu XH, Yuan HJ, Kang Y, Jiao JJ, Gao WZ, et al. Noninvasive delayed limb ischemic preconditioning attenuates myocardial ischemia-reperfusion injury in rats by a mitochondrial K(ATP) channel-dependent mechanism [J]. Physiol Res,2011,60(2):271-279.
[122]Zatta AJ, Kin H, Lee G, Wang N, Jiang R, Lust R, Reeves JG, et al. Infarct-sparing effect of myocardial postconditioning is dependent on protein kinase C signalling [J]. Cardiovasc Res,2006,70(2):315-324.
[123]Ferrera R, Larese A, Berthod F, Guidollet J, Rodriguez C, Dureau G, Dittmar A. Quantitative reduction of MTT by hearts biopsies in vitro is an index of viability [J]. J Mol Cell Cardiol,1993,25(9):1091-1099.
[124]Schwarz ER, Somoano Y, Hale SL, Kloner RA. What is the required reperfusion period for assessment of myocardial infarct size using triphenyltetrazolium chloride staining in the rat? [J]. J Thromb Thrombolysis,2000,10(2):181-187.
[125]Fruman DA, Cantley LC. Phosphoinositide 3-kinase in immunological systems [J]. Semin Immunol,2002,14(1):7-18.
[126]Coffer PJ, Woodgett JR. Molecular cloning and characterisation of a novel putative protein-serine kinase related to the cAMP-dependent and protein kinase C families [J]. Eur J Biochem,1991,201(2):475-481.
[127]Hers I, Vincent EE, Tavare JM. Akt signalling in health and disease [J]. Cell Signal, 2011,23(10):1515-1527.
[128]Altomare DA, Guo K, Cheng JQ, Sonoda G, Walsh K, Testa JR. Cloning, chromosomal localization and expression analysis of the mouse Akt2 oncogene [J]. Oncogene,1995, 11(6):1055-1060.
[129]Altomare DA, Lyons GE, Mitsuuchi Y, Cheng JQ, Testa JR. Akt2 mRNA is highly expressed in embryonic brown fat and the AKT2 kinase is activated by insulin [J]. Oncogene,1998,16(18):2407-2411.
[130]Hemmings BA. Akt signaling:linking membrane events to life and death decisions [J]. Science,1997,275(5300):628-630.
[131]Downward J. Mechanisms and consequences of activation of protein kinase B/Akt [J]. Curr Opin Cell Biol,1998,10(2):262-267.
[132]Camper-Kirby D, Welch S, Walker A, Shiraishi I, Setchell KD, Schaefer E, Kajstura J, et al. Myocardial Akt activation and gender:increased nuclear activity in females versus males [J]. Circ Res,2001,88(10):1020-1027.
[133]Andjelkovic M, Jakubowicz T, Cron P, Ming XF, Han JW, Hemmings BA. Activation and phosphorylation of a pleckstrin homology domain containing protein kinase (RAC-PK/PKB) promoted by serum and protein phosphatase inhibitors [J]. Proc Natl Acad Sci U S A,1996,93(12):5699-5704.
[134]Brazil DP, Yang Z.Z, Hemmings BA. Advances in protein kinase B signalling: AKTion on multiple fronts [J]. Trends Biochem Sci,2004,29(5):233-242.
[135]Brazil DP, Park J, Hemmings BA. PKB binding proteins. Getting in on the Akt [J]. Cell,2002,111(3):293-303.
[136]Shiojima I, Walsh K. Role of Akt signaling in vascular homeostasis and angiogenesis [J]. Circ Res,2002,90(12):1243-1250.
[137]Vivanco I, Sawyers CL. The phosphatidylinositol 3-Kinase AKT pathway in human cancer [J]. Nat Rev Cancer,2002,2(7):489-501.
[138]Woodgett JR. Recent advances in the protein kinase B signaling pathway [J]. Curr Opin Cell Biol,2005,17(2):150-157.
[139]Dufour C, Holy X, Marie PJ. Transforming growth factor-β prevents osteoblast apoptosis induced by skeletal unloading via PI3K/Akt, Bcl-2, and phospho-Bad signaling [J]. Am J Physiol Endocrinol Metab,2008,294(4):E794-E801.
[140]Jones RG, Saibil SD, Pun JM, Elford AR, Bonnard M, Pellegrini M, Arya S, et al. NF-κB couples protein kinase B/Akt signaling to distinct survival pathways and the regulation of lymphocyte homeostasis in vivo [J]. J Immunol,2005, 175(6):3790-3799.
[141]Tsang A, Hausenloy DJ, Mocanu MM, Carr RD, Yellon DM. Preconditioning the diabetic heart:the importance of Akt phosphorylation [J]. Diabetes,2005, 54(8):2360-2364.
[142]Bopassa JC, Ferrera R, Gateau-Roesch O, Couture-Lepetit E, Ovize M. PI 3-kinase regulates the mitochondrial transition pore in controlled reperfusion and postconditioning [J]. Cardiovasc Res,2006,69(1):178-185.
[143]Aggarwal BB, Kunnumakkara AB, Harikumar KB, Gupta SR, Tharakan ST, Koca C, Dey S, et al. Signal transducer and activator of transcription-3, inflammation, and cancer:how intimate is the relationship? [J]. Ann N Y Acad Sci,2009, 1171:59-76.
[144]Hilfiker-Kleiner D, Hilfiker A, Fuchs M, Kaminski K, Schaefer A, Schieffer B, Hillmer A, et al. Signal transducer and activator of transcription 3 is required for myocardial capillary growth, control of interstitial matrix deposition, and heart protection from ischemic injury [J]. Circ Res,2004,95(2):187-195.
[145]Snyder M, Huang XY, Zhang JJ. Identification of novel direct Stat3 target genes for control of growth and differentiation [J]. J Biol Chem,2008,283(7):3791-3798.
[146]Meldrum DR. Tumor necrosis factor in the heart [J]. Am J Physiol,1998,274(3 Pt 2):R577-R595.
[147]Dawn B, Xuan YT, Guo Y, Rezazadeh A, Stein AB, Hunt G, Wu WJ, et al. IL-6 plays an obligatory role in late preconditioning via JAK-STAT signaling and upregulation of iNOS and COX-2 [J]. Cardiovasc Res,2004,64(1):61-71.
[148]Ananthakrishnan R, Hallam K, Li Q, Ramasamy R. JAK-STAT pathway in cardiac ischemic stress [J]. Vascul Pharmacol,2005,43(5):353-356.
[149]Osugi T, Oshima Y, Fujio Y, Funamoto M, Yamashita A, Negoro S, Kunisada K, et al. Cardiac-specific activation of signal transducer and activator of transcription 3 promotes vascular formation in the heart [J]. J Biol Chem,2002,277(8):6676-6681.
[150]Hattori R, Maulik N, Otani H, Zhu L, Cordis G, Engelman RM, Siddigui MA, et al. Role of STAT3 in ischemic preconditioning [J]. J Mol Cell Cardiol,2001, 33(11):1929-1936.
[151]Smith RM, Suleman N, Lacerda L, Opie LH, Akira S, Chien KR, Sack MN. Genetic depletion of cardiac myocyte STAT-3 abolishes classical preconditioning [J]. Cardiovasc Res,2004,63(4):611-616.
[152]Uemura K, Li M, Tsutsumi T, Yamazaki T, Kawada T, Kamiya A, Inagaki M, et al. Efferent vagal nerve stimulation induces tissue inhibitor of metalloproteinase-1 in myocardial ischemia-reperfusion injury in rabbit [J]. Am J Physiol Heart Circ Physiol,2007,293(4):H2254-H2261.
[153]Xiong J, Xue FS, Yuan YJ, Wang Q, Liao X, Wang WL. Cholinergic anti-inflammatory pathway:a possible approach to protect against myocardial ischemia reperfusion injury [J]. Chin Med J (Engl),2010,123(19):2720-2726.
[154]Steffens S, Montecucco F, Mach F. The inflammatory response as a target to reduce myocardial ischaemia and reperfusion injury [J]. Thromb Haemost,2009, 102(2):240-247.
[155]Li C, Gao Y, Tian J, Shen J, Xing Y, Liu Z. Sophocarpine administration preserves myocardial function from ischemia-reperfusion in rats via NF-κB inactivation [J]. J Ethnopharmacol,2011,135(3):620-625.
[156]Tsao PS, Aoki N, Lefer DJ, Johnson G, Lefer AM. Time course of endothelial dysfunction and myocardial injury during myocardial ischemia and reperfusion in the cat [J]. Circulation,1990,82(4):1402-1412.
[157]Liang F, Gao E, Tao L, Liu H, Qu Y, Christopher TA, Lopez BL, et al. Critical timing of L-arginine treatment in post-ischemic myocardial apoptosis-role of NOS isoforms [J]. Cardiovasc Res,2004,62(3):568-577.
[158]Zimmerman J, Fromm R, Meyer D, Boudreaux A, Wun CC, Smalling R, Davis B, et al. Diagnostic marker cooperative study for the diagnosis of myocardial infarction [J]. Circulation,1999,99(13):1671-1677.
[159]Howie-Esquivel J, White M. Biomarkers in acute cardiovascular disease [J]. J Cardiovasc Nurs,2008,23(2):124-131.
[160]Tsung JS, Tsung SS. Creatine kinase isoenzymes in extracts of various human skeletal muscles [J]. Clin Chem,1986,32(8):1568-1570.
[161]Mair J. Cardiac troponin I and troponin T:are enzymes still relevant as cardiac markers? [J]. Clin Chim Acta,1997,257(1):99-115.
[162]Newby LK, Rodriguez I, Finkle J, Becher RC, Hicks KA, Hausner E, Chesler R, et al. Troponin measurements during drug development--considerations for monitoring and management of potential cardiotoxicity:an educational collaboration among the Cardiac Safety Research Consortium, the Duke Clinical Research Institute, and the US Food and Drug Administration [J]. Am Heart J,2011, 162(1):64-73.
[163]Thygesen K, Alpert JS, White HD. Universal definition of myocardial infarction [J]. Eur Heart J,2007,28(20):2525-2538.
[164]Babuin L, Jaffe AS. Troponin:the biomarker of choice for the detection of cardiac injury [J]. CMAJ,2005,173(10):1191-1202.
[165]Antman EM, Tanasijevic MJ, Thompson B, Schactman M, Mccabe CH, Cannon CP, Fischer GA, et al. Cardiac-specific troponin I levels to predict the risk of mortality in patients with acute coronary syndromes [J]. N Engl J Med,1996, 335(18):1342-1349.
[166]Solaro RJ, Arteaga GM. Heart failure, ischemia/reperfusion injury and cardiac troponin [J]. Adv Exp Med Biol,2007,592:191-200.
[167]Huang WH, Lee JF, Wang D, Gou WH, Chang CY, Wei J. Postischemia myocardial injury in coronary artery bypass patients (PP6) [J]. Transplant Proc, 2010,42(3):725-728.
[168]Jeremias A, Gibson CM. Narrative review:alternative causes for elevated cardiac troponin levels when acute coronary syndromes are excluded [J]. Ann Intern Med, 2005,142(9):786-791.
[169]Saenger AK, Jaffe AS. Requiem for a heavyweight:the demise of creatine kinase-MB [J]. Circulation,2008,118(21):2200-2206.
[170]Hu X, Jiang H, Ma F, Xu C, Bo C, Wen H, Wu B, et al. Similarities between ischemic preconditioning and postconditioning in myocardial ischemia/reperfusion injury [J]. Int J Cardiol,2010,144(1):135-136.
[171]Dai AL, Fan LH, Zhang FJ, Yang MJ, Yu J, Wang JK, Fang T, et al. Effects of sevoflurane preconditioning and postconditioning on rat myocardial stunning in ischemic reperfusion injury [J]. J Zhejiang Univ Sci B,2010,11(4):267-274.
[172]Zipes DP, Wellens HJ. Sudden cardiac death [J]. Circulation,1998, 98(21):2334-2351.
[173]Matejikova J, Ravingerova T, Pancza D, Carnicka S, Kolar F. Mitochondrial KATP opening confers protection against lethal myocardial injury and ischaemia-induced arrhythmias in the rat heart via PI3K/Akt-dependent and-independent mechanisms [J]. Can J Physiol Pharmacol,2009,87(12):1055-1062.
[174]Mackins CJ, Kano S, Seyedi N, Schafer U, Reid AC, Machida T, Silver RB, et al. Cardiac mast cell-derived renin promotes local angiotensin formation, norepinephrine release, and arrhythmias in ischemia/reperfusion [J]. J Clin Invest, 2006,116(4):1063-1070.
[175]Dennis SC, Coetzee WA, Cragoe EJ Jr, Opie LH. Effects of proton buffering and of amiloride derivatives on reperfusion arrhythmias in isolated rat hearts. Possible evidence for an arrhythmogenic role of Na(+)-H+ exchange [J]. Circ Res,1990, 66(4):1156-1159.
[176]Wit AL, Janse MJ. Reperfusion arrhythmias and sudden cardiac death:a century of progress toward an understanding of the mechanisms [J]. Circ Res,2001, 89(9):741-743.
[177]Ravingerova T, Matejikova J, Pancza D, Kolar F. Reduced susceptibility to ischemia-induced arrhythmias in the preconditioned rat heart is independent of PI3-kinase/Akt [J]. Physiol Res,2009,58(3):443-447.
[178]Ogawa K, Ikewaki K, Taniguchi I, Takatsuka H, Mori C, Sasaki H, Okazaki F, et al. Mitiglinide, a novel oral hypoglycemic agent, preserves the cardioprotective effect of ischemic preconditioning in isolated perfused rat hearts [J]. Int Heart J, 2007,48(3):337-345.
[179]Das B, Sarkar C. Similarities between ischemic preconditioning and 17β-estradiol mediated cardiomyocyte KATP channel activation leading to cardioprotective and antiarrhythmic effects during ischemia/reperfusion in the intact rabbit heart [J]. J Cardiovasc Pharmacol,2006,47(2):277-286.
[180]Wu ZK, Iivainen T, Pehkonen E, Laurikka J, Tarkka MR. Ischemic preconditioning suppresses ventricular tachyarrhythmias after myocardial revascularization [J]. Circulation,2002,106(24):3091-3096.
[181]Chen Z, Luo H, Zhuang M, Cai L, Su C, Lei Y, Zou J. Effects of ischemic preconditioning on ischemia/reperfusion-induced arrhythmias by upregulatation of connexin 43 expression [J]. J Cardiothorac Surg,2011,6:80.
[182]Danik SB, Liu F, Zhang J, Suk HJ, Morley GE, Fishman GI, Gutstein DE. Modulation of cardiac gap junction expression and arrhythmic susceptibility [J]. Circ Res,2004,95(10):1035-1041.
[183]Koda K, Salazar-Rodriguez M, Corti F, Chan NY, Estephan R, Silver RB, Mochly-Rosen D, et al. Aldehyde dehydrogenase activation prevents reperfusion arrhythmias by inhibiting local renin release from cardiac mast cells [J]. Circulation,2010,122(8):771-781.
[184]Babai L, Papp JG, Parratt JR, Vegh A. The antiarrhythmic effects of ischaemic preconditioning in anaesthetized dogs are prevented by atropine; role of changes in baroreceptor reflex sensitivity [J]. Br J Pharmacol,2002,135(1):55-64.
[185]Zuanetti G, De Ferrari GM, Priori SG, Schwartz PJ. Protective effect of vagal stimulation on reperfusion arrhythmias in cats [J]. Circ Res,1987,61(3):429-435.
[186]Ando M, Katare RG, Kakinuma Y, Zhang D, Yamasaki F, Muramoto K, Sato T. Efferent vagal nerve stimulation protects heart against ischemia-induced arrhythmias by preserving connexin43 protein [J]. Circulation,2005, 112(2):164-170.
[187]Zipes DP, Rubart M. Neural modulation of cardiac arrhythmias and sudden cardiac death [J]. Heart Rhythm,2006,3(1):108-113.
[188]Ng GA, Brack KE, Patel VH, Coote JH. Autonomic modulation of electrical restitution, alternans and ventricular fibrillation initiation in the isolated heart [J]. Cardiovasc Res,2007,73(4):750-760.
[189]Jiang H, Hu X, Lu Z, Wen H, Zhao D, Tang Q, Yang B. Effects of sympathetic nerve stimulation on ischemia-induced ventricular arrhythmias by modulating connexin43 in rats [J]. Arch Med Res,2008,39(7):647-654.
[190]Kawaguchi M, Takahashi M, Hata T, Kashima Y, Usui F, Morimoto H, Izawa A, et al. Inflammasome activation of cardiac fibroblasts is essential for myocardial ischemia/reperfusion injury [J]. Circulation,2011,123(6):594-604.
[191]Black RA, Rauch CT, Kozlosky CJ, Peschon JJ, Slack JL, Wolfson MF, Castner BJ, et al. A metalloproteinase disintegrin that releases tumour-necrosis factor-a from cells [J]. Nature,1997,385(6618):729-733.
[192]Zhang C, Xu X, Potter BJ, Wang W, Kuo L, Michae L, Bagby GL, et al. TNF-a contributes to endothelial dysfunction in ischemia/reperfusion injury [J]. Arterioscler Thromb Vase Biol,2006,26(3):475-480.
[193]Zhang C, Wu J, Xu X, Potter BJ, Gao X. Direct relationship between levels of TNF-α expression and endothelial dysfunction in reperfusion injury [J]. Basic Res Cardiol,2010,105(4):453-464.
[194]Gao X, Zhang H, Belmadani S, Wu J, Xu X, Elford H, Potter BJ, et al. Role of TNF-a-induced reactive oxygen species in endothelial dysfunction during reperfusion injury [J]. Am J Physiol Heart Circ Physiol,2008, 295(6):H2242-H2249.
[195]Yamada S, Maruyama I. HMGB1, a novel inflammatory cytokine [J]. Clin Chim Acta,2007,375(1-2):36-42.
[196]Ulloa L, Messmer D. High-mobility group box 1 (HMGB1) protein:friend and foe [J]. Cytokine Growth Factor Rev,2006,17(3):189-201.
[197]Li W, Sama AE, Wang H. Role of HMGB1 in cardiovascular diseases [J]. Curr Opin Pharmacol,2006,6(2):130-135.
[198]Andrassy M, Volz HC, Igwe JC, Funke B, Eichberger SN, Kaya Z, Buss S, et al. High-mobility group box-1 in ischemia-reperfusion injury of the heart [J]. Circulation,2008,117(25):3216-3226.
[199]Kalawski R, Majewski M, Kaszkowiak E, Wysocki H, Siminiak T. Transcardiac release of soluble adhesion molecules during coronary artery bypass grafting: effects of crystalloid and blood cardioplegia [J]. Chest,2003,123(5):1355-1360.
[200]Metzler B, Mair J, Lercher A, Schaber C, Hintringer F, Pachinger O, Xu Q. Mouse model of myocardial remodelling after ischemia:role of intercellular adhesion molecule-1 [J]. Cardiovasc Res,2001,49(2):399-407.
[201]Murohara T, Kamijikkoku S, Honda T. Increased circulating soluble intercellular adhesion molecule-1 in acute myocardial infarction:a possible predictor of reperfusion ventricular arrhythmias [J]. Crit Care Med,2000,28(6):1861-1864.
[202]Bujak M, Dobaczewski M, Chatila K, Mendoza LH, Li N, Reddy A, Frangogiannis NG. Interleukin-1 receptor type I signaling critically regulates infarct healing and cardiac remodeling [J]. Am J Pathol,2008,173(1):57-67.
[203]Abbate A, Van Tassell BW, Seropian IM, Toldo S, Robati R, Varma A, Salloum FN, et al. Interleukin-1β modulation using a genetically engineered antibody prevents adverse cardiac remodelling following acute myocardial infarction in the mouse [J]. Eur J Heart Fail,2010,12(4):319-322.
[204]Abbate A, Kontos MC, Grizzard JD, Biondi-Zoccai GG, Van Tassell BW, Robati R, Roach LM, et al. Interleukin-1 blockade with anakinra to prevent adverse cardiac remodeling after acute myocardial infarction (Virginia Commonwealth University Anakinra Remodeling Trial [VCU-ART] Pilot study) [J]. Am J Cardiol,2010, 105(10):1371-1377.
[205]Akiyama D, Hara T, Yoshitomi O, Maekawa T, Cho S, Sumikawa K. Postischemic infusion of sivelestat sodium hydrate, a selective neutrophil elastase inhibitor, protects against myocardial stunning in swine [J]. J Anesth,2010,24(4):575-581.
[206]Loubele ST, Spek CA, Leenders P, van Oerle R, Aberson HL, van der Voort D, Hamulyak K, et al. Active site inhibited factor Ⅶa attenuates myocardial ischemia/reperfusion injury in mice [J]. J Thromb Haemost,2009,7(2):290-298.
[207]Sawa Y, Ichikawa H, Kagisaki K, Ohata T, Matsuda H. Interleukin-6 derived from hypoxic myocytes promotes neutrophil-mediated reperfusion injury in myocardium [J]. J Thorac Cardiovasc Surg,1998,116(3):511-517.
[208]Yang Z, Zingarelli B, Szabo C. Crucial role of endogenous interleukin-10 production in myocardial ischemia/reperfusion injury [J]. Circulation,2000, 101(9):1019-1026.
[209]Pasqui AL, Di Renzo M, Maffei S, Pastorelli M, Pompella G, Auteri A, Puccetti L. Pro/Anti-inflammatory cytokine imbalance in postischemic left ventricular remodeling [J]. Mediators Inflamm,2010,2010:974694.
[210]Sabat R, Grutz G, Warszawska K, Kirsch S, Witte E, Wolk K, Geginat J. Biology of interleukin-10 [J]. Cytokine Growth Factor Rev,2010,21(5):331-344.
[211]Hiasa G, Hamada M, Ikeda S, Hiwada K. Ischemic preconditioning and lipopolysaccharide attenuate nuclear factor-κB activation and gene expression of inflammatory cytokines in the ischemia-reperfused rat heart [J]. Jpn Circ J,2001, 65(11):984-990.
[212]Xiong J, Wang Q, Xue FS, Yuan YJ, Li S, Liu JH, Liao X, et al. Comparison of cardioprotective and anti-inflammatory effects of ischemia pre- and postconditioning in rats with myocardial ischemia-reperfusion injury [J]. Inflamm Res,2011,60(6):547-554.
[213]Hausenloy DJ, Yellon DM. The therapeutic potential of ischemic conditioning:an update [J]. Nat Rev Cardiol,2011,8(11):619-629.
[214]Hausenloy DJ, Yellon DM. Remote ischaemic preconditioning:underlying mechanisms and clinical application [J]. Cardiovasc Res,2008,79(3):377-386.
[215]Larsen JR, Aagaard S, Lie RH, Sloth E, Hasenkam JM. Sevoflurane improves myocardial ischaemic tolerance in a closed-chest porcine model [J]. Acta Anaesthesiol Scand,2008,52(10):1400-1410.
[216]Konstantinov IE, Arab S, Kharbanda RK, Li J, Cheung MM, Cherepanov V, Downey GP, et al. The remote ischemic preconditioning stimulus modifies inflammatory gene expression in humans [J]. Physiol Genomics,2004, 19(1):143-150.
[217]Li CM, Zhang XH, Ma XJ, Luo M. Limb ischemic postconditioning protects myocardium from ischemia-reperfusion injury [J]. Scand Cardiovasc J,2006, 40(5):312-317.
[218]Osswald H, Moerike K. Remote conditioning in clinical practice:a type of distant healing? [J]. Cardiology,2011,119(4):214-216.
[219]Pavlov VA, Tracey KJ. The cholinergic anti-inflammatory pathway [J]. Brain Behav Immun,2005,19(6):493-499.
[220]Tracey KJ. The inflammatory reflex [J]. Nature,2002,420(6917):853-859.
[221]Williams DL, Li C, Ha T, Ozment-Skelton T, Kalbfleisch JH, Preiszner J, Brooks L, et al. Modulation of the phosphoinositide 3-kinase pathway alters innate resistance to polymicrobial sepsis [J]. J Immunol,2004,172(1):449-456.
[222]Guha M, Mackman N. The phosphatidylinositol 3-kinase-Akt pathway limits lipopolysaccharide activation of signaling pathways and expression of inflammatory mediators in human monocytic cells [J]. J Biol Chem,2002,277(35):32124-32132.
[223]Fukao T, Koyasu S. PI3K and negative regulation of TLR signaling [J]. Trends Immunol,2003,24(7):358-363.
[224]Li C, Ha T, Kelley J, Gao X, Qiu Y, Kao RL, Browder W, et al. Modulating Toll-like receptor mediated signaling by (1-->3)-β-D-glucan rapidly induces cardioprotection [J]. Cardiovasc Res,2004,61(3):538-547.
[225]Ernst M, Najdovska M, Grail D, Lundgen-May T, Buchert M, Tye H, Matthews VB, et al. STAT3 and STAT1 mediate IL-11-dependent and inflammation-associated gastric tumorigenesis in gpl30 receptor mutant mice [J]. J Clin Invest,2008,118(5):1727-1738.
[226]Wang M, Zhang W, Crisostomo P, Markel T, Meldrum KK, Fu XY, Meldrum DR. Endothelial STAT3 plays a critical role in generalized myocardial proinflammatory and proapoptotic signaling [J]. Am J Physiol Heart Circ Physiol,2007, 293(4):H2101-H2108.
[227]Goodman MD, Koch SE, Fuller-Bicer GA, Butler KL. Regulating RISK:a role for JAK-STAT signaling in postconditioning? [J]. Am J Physiol Heart Circ Physiol, 2008,295(4):H1649-H1656.
[228]Matsui T, Li L, Wu JC, Cook SA, Nagoshi T, Picard MH, Liao R, et al. Phenotypic spectrum caused by transgenic overexpression of activated Akt in the heart [J]. J Biol Chem,2002,277(25):22896-22901.
[229]Shioi T, McMullen JR, Kang PM, Douglas PS, Obata T, Franke TF, Cantley LC, et al. Akt/protein kinase B promotes organ growth in transgenic mice [J]. Mol Cell Biol,2002,22(8):2799-2809.
[230]Malstrom S, Tili E, Kappes D, Ceci JD, Tsichlis PN. Tumor induction by an Lck-MyrAkt transgene is delayed by mechanisms controlling the size of the thymus [J]. Proc Natl Acad Sci U S A,2001,98(26):14967-14972.
[231]Tuttle RL, Gill NS, Pugh W, Lee JP, Koeberlein B, Furth EE, Polonsky KS, et al. Regulation of pancreatic β-cell growth and survival by the serine/threonine protein kinase Aktl/PKBa [J]. Nat Med,2001,7(10):1133-1137.
[232]Bernal-Mizrachi E, Wen W, Stahlhut S, Welling CM, Permutt MA. Islet β cell expression of constitutively active Aktl/PKB a induces striking hypertrophy, hyperplasia, and hyperinsulinemia [J]. J Clin Invest,2001,108(11):1631-1638.
[233]Schwertfeger KL, McManaman JL, Palmer CA, Neville MC, Anderson SM. Expression of constitutively activated Akt in the mammary gland leads to excess lipid synthesis during pregnancy and lactation [J]. J Lipid Res,2003, 44(6):1100-1112.
[234]Datta SR, Brunet A, Greenberg ME. Cellular survival:a play in three Akts [J]. Genes Dev,1999,13(22):2905-2927.
[235]Mangi AA, Noiseux N, Kong D, He H, Rezvani M, Ingwall JS, Dzau VJ. Mesenchymal stem cells modified with Akt prevent remodeling and restore performance of infarcted hearts [J]. Nat Med,2003,9(9):1195-1201.
[236]Tong H, Imahashi K, Steenbergen C, Murphy E. Phosphorylation of glycogen synthase kinase-3β during preconditioning through a phosphatidylinositol-3-kinase-dependent pathway is cardioprotective [J]. Circ Res, 2002,90(4):377-379.
[237]Ban K, Cooper AJ, Samuel S, Bhatti A, Patel M, Izumo S, Penninger JM, et al. Phosphatidylinositol 3-kinase gamma is a critical mediator of myocardial ischemic and adenosine-mediated preconditioning [J]. Circ Res,2008,103(6):643-653.
[238]Kunuthur SP, Mocanu MM, Hemmings BA, Hausenloy DJ, Yellon DM. The Aktl isoform is an essential mediator of ischemic preconditioning [J]. J Cell Mol Med, 2011 [Epub ahead of print].
[239]Hausenloy DJ, Yellon DM. Survival kinases in ischemic preconditioning and postconditioning [J]. Cardiovasc Res,2006,70(2):240-253.
[240]Heusch G, Boengler K, Schulz R. Inhibition of mitochondrial permeability transition pore opening:the Holy Grail of cardioprotection [J]. Basic Res Cardiol, 2010,105(2):151-154.
[241]Juhaszova M, Zorov DB, Kim SH, Pepe S, Fu Q, Fishbein KW, Ziman BD, et al. Glycogen synthase kinase-3β mediates convergence of protection signaling to inhibit the mitochondrial permeability transition pore [J]. J Clin Invest,2004, 113(11):1535-1549.
[242]Li J, Xuan W, Yan R, Tropak MB, Jean-St-Michel E, Liang W, Gladstone R, et al. Remote preconditioning provides potent cardioprotection via PI3K/Akt activation and is associated with nuclear accumulation of β-catenin [J]. Clin Sci (Lond),2011, 120(10):451-462.
[243]Rahman S, Li J, Bopassa JC, Umar S, Iorga A, Partownavid P, Eghbali M. Phosphorylation of GSK-3β mediates intralipid-induced cardioprotection against ischemia/reperfusion injury [J]. Anesthesiology,2011,115(2):242-253.
[244]Fang SJ, Wu XS, Han ZH, Zhang XX, Wang CM, Li XY, Lu LQ, et al. Neuregulin-1 preconditioning protects the heart against ischemia/reperfusion injury through a PI3K/Akt-dependent mechanism [J]. Chin Med J (Engl),2010, 123(24):3597-3604.
[245]Zhou H, Hou SZ, Luo P, Zeng B, Wang JR, Wong YF, Jiang ZH, et al. Ginseng protects rodent hearts from acute myocardial ischemia-reperfusion injury through GR/ER-activated RISK pathway in an endothelial NOS-dependent mechanism [J]. J Ethnopharmacol,2011,135(2):287-298.
[246]Huang MH, Wu Y, Nguyen V, Rastogi S, Mcconnell BK, Wijaya C, Uretsky BF, et al. Heart protection by combination therapy with esmolol and milrinone at late-ischemia and early reperfusion [J]. Cardiovasc Drugs Ther,2011, 25(3):223-232.
[247]Boengler K, Hilfiker-Kleiner D, Drexler H, Heusch G, Schulz R. The myocardial JAK/STAT pathway:from protection to failure [J]. Pharmacol Ther,2008, 120(2):172-185.
[248]Akira S, Nishio Y, Inoue M, Wang XJ, Wei S, Matsusaka T, Yoshida K, et al. Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway [J]. Cell, 1994,77(1):63-71.
[249]Cao X, Tay A, Guy GR, Tan YH. Activation and association of Stat3 with Src in v-Src-transformed cell lines [J]. Mol Cell Biol,1996,16(4):1595-1603.
[250]Vignais ML, Sadowski HB, Watling D, Rogers NC, Gilman M. Platelet-derived growth factor induces phosphorylation of multiple JAK family kinases and STAT proteins [J]. Mol Cell Biol,1996,16(4):1759-1769.
[251]Yu CL, Meyer DJ, Campbell GS, Larner AC, Carter-Su C, Schwartz J, Jove R. Enhanced DNA-binding activity of a Stat3-related protein in cells transformed by the Src oncoprotein [J]. Science,1995,269(5220):81-83.
[252]Giordano V, De Falco G, Chiari R, Quinto I, Pelicci PG, Bartholomew L, Delmastro P, et al. Shc mediates IL-6 signaling by interacting with gp130 and Jak2 kinase [J]. J Immunol,1997,158(9):4097-4103.
[253]Garcia R, Yu CL, Hudnall A, Catlett R, Nelson KL, Smithgall T, Fujita DJ, et al. Constitutive activation of Stat3 in fibroblasts transformed by diverse oncoproteins and in breast carcinoma cells [J]. Cell Growth Differ,1997,8(12):1267-1276.
[254]Lutticken C, Wegenka UM, Yuan J, Buschmann J, Schindler C, Ziemiecki A, Harpur AG, et al. Association of transcription factor APRF and protein kinase Jakl with the interleukin-6 signal transducer gp130 [J]. Science,1994,263(5143):89-92.
[255]Tian SS, Tapley P, Sincich C, Stein RB, Rosen J, Lamb P. Multiple signaling pathways induced by granulocyte colony-stimulating factor involving activation of JAKs, STAT5, and/or STAT3 are required for regulation of three distinct classes of immediate early genes [J]. Blood,1996,88(12):4435-4444.
[256]Migone TS, Lin JX, Cereseto A, Mulloy JC, O'shea JJ, Franchini G, Leonard WJ. Constitutively activated Jak-STAT pathway in T cells transformed with HTLV-I [J]. Science,1995,269(5220):79-81.
[257]Megeney LA, Perry RL, LeCouter JE, Rudnicki MA. bFGF and LIF signaling activates STAT3 in proliferating myoblasts [J]. Dev Genet,1996,19(2):139-145.
[258]Boengler K, Hilfiker-Kleiner D, Heusch G, Schulz R. Inhibition of permeability transition pore opening by mitochondrial STAT3 and its role in myocardial ischemia/reperfusion [J]. Basic Res Cardiol,2010,105(6):771-785.
[259]Bolli R, Stein AB, Guo Y, Wang OL, Rokosh G, Dawn B, Molkentin JD, et al. A murine model of inducible, cardiac-specific deletion of STAT3:its use to determine the role of STAT3 in the upregulation of cardioprotective proteins by ischemic preconditioning [J]. J Mol Cell Cardiol,2011,50(4):589-597.
[260]Tian Y, Zhang W, Xia D, Modi P, Liang D, Wei M. Postconditioning inhibits myocardial apoptosis during prolonged reperfusion via a JAK2-STAT3-Bcl-2 pathway [J]. J Biomed Sci,2011,18:53.
[261]Boengler K, Buechert A, Heinen Y, Roeskes C, Hilfiker-Kleiner D, Heusch G, Schulz R. Cardioprotection by ischemic postconditioning is lost in aged and STAT3-deficient mice [J]. Circ Res,2008,102(1):131-135.
[262]Kelly RF, Lamont KT, Somers S, Hacking D, Lacerda L, Thomas P, Opie LH, et al. Ethanolamine is a novel STAT-3 dependent cardioprotective agent [J]. Basic Res Cardiol,2010,105(6):763-770.
[263]Wang M, Wang Y, Abarbanell A, Tan J, Weil B, Herrmann J, Meldrum DR. Both endogenous and exogenous testosterone decrease myocardial STAT3 activation and SOCS3 expression after acute ischemia and reperfusion [J]. Surgery,2009, 146(2):138-144.
[264]Baker JE, Su J, Hsu A, Shi Y, Zhao M, Strande JL, Fu X, et al. Human thrombopoietin reduces myocardial infarct size, apoptosis, and stunning following ischaemia/reperfusion in rats [J]. Cardiovasc Res,2008,77(1):44-53.
[265]Gross ER, Hsu AK, Gross GJ. The JAK/STAT pathway is essential for opioid-induced cardioprotection:JAK2 as a mediator of STAT3, Akt, and GSK-3β [J]. Am J Physiol Heart Circ Physiol,2006,291(2):H827-H834.
[266]Li X, Mikhalkova D, Gao E, Zhang J, Myers V, Zincarelli C, Lei Y, et al. Myocardial injury after ischemia-reperfusion in mice deficient in Akt2 is associated with increased cardiac macrophage density [J]. Am J Physiol Heart Circ Physiol, 2011,301(5):H1932-H1940.
[267]Pfitzner E, Kliem S, Baus D, Litterst CM. The role of STATs in inflammation and inflammatory diseases [J]. Curr Pharm Des,2004,10(23):2839-2850.
[268]Zhong Z, Wen Z, Darnell JJ. Stat3:a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6 [J]. Science,1994,264(5155):95-98.
[269]Dalwadi H, Krysan K, Heuze-Vourc'H N, Dohadwala M, Elashoff D, Sharma S, Cacalano N, et al. Cyclooxygenase-2-dependent activation of signal transducer and activator of transcription 3 by interleukin-6 in non-small cell lung cancer [J]. Clin Cancer Res,2005, 11(21):7674-7682.
[270]Calvillo L, Vanoli E, Andreoli E, Besana A, Omodeo E, Gnecchi M, Zerbi P, et al. Vagal stimulation, through its nicotinic action, limits infarct size and the inflammatory response to myocardial ischemia and reperfusion [J]. J Cardiovasc Pharmacol,2011,58(5):500-507.
[271]Maroko PR, Kjekshus JK, Sobel BE, Watanabe T, Covell JW, Ross J Jr, Braunwald E. Factors influencing infarct size following experimental coronary artery occlusions [J]. Circulation,1971,43(1):67-82.
[272]Redwood DR, Smith ER, Epstein SE. Coronary artery occlusion in the conscious dog. Effects of alterations in heart rate and arterial pressure on the degree of myocardial ischemia [J]. Circulation,1972,46(2):323-332.
[273]Wu AH, Parsons L, Every NR, Bates ER. Hospital outcomes in patients presenting with congestive heart failure complicating acute myocardial infarction:a report from the Second National Registry of Myocardial Infarction (NRMI-2) [J]. J Am Coll Cardiol,2002,40(8):1389-1394.
[274]Cury RC, Techasith T, Feuchtner G, Dabus G. Cardiovascular disease and stroke in women:role of radiology [J]. AJR Am J Roentgenol,2011,196(2):265-273.
[275]Zhang XH, Lu ZL, Liu L. Coronary heart disease in China [J]. Heart,2008, 94(9):1126-1131.
[276]Gaziano TA, Bitton A, Anand S, Abrahams-Gessel S, Murphy A. Growing epidemic of coronary heart disease in low- and middle-income countries [J]. Curr Probl Cardiol,2010,35(2):72-115.
[277]Nallamothu B, Fox KA, Kennelly BM, Van de Werf F, Gore JM, Steg PG, Granger CB, et al. Relationship of treatment delays and mortality in patients undergoing fibrinolysis and primary percutaneous coronary intervention. The Global Registry of Acute Coronary Events [J]. Heart,2007,93(12):1552-1555.
[278]Armstrong PW, Westerhout CM, Welsh RC. Duration of symptoms is the key modulator of the choice of reperfusion for ST-elevation myocardial infarction [J]. Circulation,2009,119(9):1293-1303.
[279]Vinten-Johansen J. Involvement of neutrophils in the pathogenesis of lethal myocardial reperfusion injury [J]. Cardiovasc Res,2004,61(3):481-497.
[280]Frangogiannis NG, Youker KA, Entman ML. The role of the neutrophil in myocardial ischemia and reperfusion [J]. EXS,1996,76:263-284.
[281]Hatchell DL, Wilson CA, Saloupis P. Neutrophils plug capillaries in acute experimental retinal ischemia [J]. Microvasc Res,1994,47(3):344-354.
[282]Gute DC, Ishida T, Yarimizu K, Korthuis RJ. Inflammatory responses to ischemia and reperfusion in skeletal muscle [J]. Mol Cell Biochem,1998,179(1-2):169-187.
[283]Rezkalla SH, Kloner RA. Coronary no-reflow phenomenon:from the experimental laboratory to the cardiac catheterization laboratory [J]. Catheter Cardiovasc Interv, 2008,72(7):950-957.
[284]Strande JL, Routhu KV, Hsu A, Nicolosi AC, Baker JE. Gadolinium decreases inflammation related to myocardial ischemia and reperfusion injury [J]. J Inflamm (Lond),2009,6:34.
[285]Nicolini FA, Mehta JL, Nichols WW, Donnelly WH, Luostarinen R, Saldeen TG. Leukocyte elastase inhibition and t-PA-induced coronary artery thrombolysis in dogs:beneficial effects on myocardial histology [J]. Am Heart J,1991, 122(5):1245-1251.
[286]Yu X, Kennedy RH, Liu SJ. JAK2/STAT3, not ERK1/2, mediates interleukin-6-induced activation of inducible nitric-oxide synthase and decrease in contractility of adult ventricular myocytes [J]. J Biol Chem,2003, 278(18):16304-16309.
[287]Romson JL, Hook BG, Kunkel SL, Abrams GD, Schork MA, Lucchesi BR. Reduction of the extent of ischemic myocardial injury by neutrophil depletion in the dog [J]. Circulation,1983,67(5):1016-1023.
[288]Jordan JE, Zhao ZQ, Vinten-Johansen J. The role of neutrophils in myocardial ischemia-reperfusion injury [J]. Cardiovasc Res,1999,43(4):860-878.
[289]Takahashi T, Hiasa Y, Ohara Y, Miyazaki S, Ogura R, Miyajima H, Yuba K, et al. Relation between neutrophil counts on admission, microvascular injury, and left ventricular functional recovery in patients with an anterior wall first acute myocardial infarction treated with primary coronary angioplasty [J]. Am J Cardiol, 2007,100(1):35-40.
[290]Dokken BB, La Bonte LR, Davis-Gorman G, Teachey MK, Seaver N, Mcdonagh PF. Glucagon-like peptide-1 (GLP-1), immediately prior to reperfusion, decreases neutrophil activation and reduces myocardial infarct size in rodents [J]. Horm Metab Res,2011,43(5):300-305.
[291]Zhang Y, Sun Q, He B, Xiao J, Wang Z, Sun X. Anti-inflammatory effect of hydrogen-rich saline in a rat model of regional myocardial ischemia and reperfusion [J]. Int J Cardiol,2011,148(1):91-95.
[292]Abdel-Rahman U, Margraf S, Aybek T, Logers T, Bitu-Moreno J, Francischetti I, Kranert T, et al. Inhibition of neutrophil activity improves cardiac function after cardiopulmonary bypass [J]. J Inflamm (Lond),2007,4:21.
[293]Hoffmeyer MR, Scalia R, Ross CR, Jones SP, Lefer DJ. PR-39, a potent neutrophil inhibitor, attenuates myocardial ischemia-reperfusion injury in mice [J]. Am J Physiol Heart Circ Physiol,2000,279(6):H2824-H2828.
[294]Feng Y, Zhao H, Xu X, Buys ES, Raher MJ, Bopassa JC, Thibault H, et al. Innate immune adaptor MyD88 mediates neutrophil recruitment and myocardial injury after ischemia-reperfusion in mice [J]. Am J Physiol Heart Circ Physiol,2008, 295(3):H1311-H1318.
[295]Zerria K, Jerbi E, Hammami S, Maaroufi A, Boubader S, Xiong JP, Arnaout MA, et al. Recombinant integrin CDllb A-domain blocks polymorphonuclear cells recruitment and protects against skeletal muscle inflammatory injury in the rat [J]. Immunology,2006,119(4):431-440.
[296]Baran KW, Nguyen M, McKendall GR, Lambrew CT, Dykstra G, Palmeri ST, Gibbons RJ, et al. Double-blind, randomized trial of an anti-CD 18 antibody in conjunction with recombinant tissue plasminogen activator for acute myocardial infarction:limitation of myocardial infarction following thrombolysis in acute myocardial infarction (LIMIT AMI) study [J]. Circulation,2001, 104(23):2778-2783.
[297]Faxon DP, Gibbons RJ, Chronos NA, Gurbel PA, Sheehan F. The effect of blockade of the CD11/CD 18 integrin receptor on infarct size in patients with acute myocardial infarction treated with direct angioplasty:the results of the HALT-MI study [J]. J Am Coll Cardiol,2002,40(7):1199-1204.
[298]Nathan C. Points of control in inflammation [J]. Nature,2002,420(6917):846-852.
[299]Venkatachalam K, Prabhu SD, Reddy VS, Boylston WH, Valente AJ, Chandrasekar B. Neutralization of interleukin-18 ameliorates ischemia/reperfusion-induced myocardial injury [J]. J Biol Chem,2009, 284(12):7853-7865.
[300]Rudolph V, Rudolph TK, Schopfer FJ, Bonacci G, Woodcock SR, Cole MP, Baker PR, et al. Endogenous generation and protective effects of nitro-fatty acids in a murine model of focal cardiac ischaemia and reperfusion [J]. Cardiovasc Res,2010, 85(1):155-166.
[301]Zhao N, Liu YY, Wang F, Hu BH, Sun K, Chang X, Pan CS, et al. Cardiotonic pills, a compound Chinese medicine, protects ischemia-reperfusion-induced microcirculatory disturbance and myocardial damage in rats [J]. Am J Physiol Heart Circ Physiol,2010,298(4):H1166-H1176.
[302]Cain BS, Meldrum DR, Dinarello CA, Meng X, Joo KS, Banerjee A, Harken AH. Tumor necrosis factor-a and interleukin-1β synergistically depress human myocardial function [J]. Crit Care Med,1999,27(7):1309-1318.
[303]Irwin MW, Mak S, Mann DL, Qu R, Penninger JM, Yan A, Dawood F, et al. Tissue expression and immunolocalization of tumor necrosis factor-a in postinfarction dysfunctional myocardium [J]. Circulation,1999,99(11):1492-1498.
[304]Siwik DA, Chang DL, Colucci WS. Interleukin-1β and tumor necrosis factor-a decrease collagen synthesis and increase matrix metalloproteinase activity in cardiac fibroblasts in vitro [J]. Circ Res,2000,86(12):1259-1265.
[305]Pevni D, Frolkis I, Shapira I, Schwartz D, Schwartz I, Chernichovski T, Nesher N, et al. Cardioplegic ischemia or reperfusion:which is a main trigger for tumor necrosis factor production? [J]. Int J Cardiol,2008,127(2):186-191.
[306]Moro C, Jouan MG, Rakotovao A, Toufektsian MC, Ormezzano O, Nagy N, Tosaki A, et al. Delayed expression of cytokines after reperfused myocardial infarction:possible trigger for cardiac dysfunction and ventricular remodeling [J]. Am J Physiol Heart Circ Physiol,2007,293(5):H3014-H3019.
[307]Deuchar GA, Opie LH, Lecour S. TNFa is required to confer protection in an in vivo model of classical ischaemic preconditioning [J]. Life Sci,2007, 80(18):1686-1691.
[308]Katare RG, Ando M, Kakinuma Y, Arikawa M, Yamasaki F, Sato T. Differential regulation of TNF receptors by vagal nerve stimulation protects heart against acute ischemic injury [J]. J Mol Cell Cardiol,2010,49(2):234-244.
[309]Gao Q, Zhang SZ, Cao CM, Bruce IC, Xia Q. The mitochondrial permeability transition pore and the Ca2+-activated K+channel contribute to the cardioprotection conferred by tumor necrosis factor-a [J]. Cytokine,2005,32(5):199-205.
[310]Kadokami T, McTiernan CF, Kubota T, Frye CS, Feldman AM. Sex-related survival differences in murine cardiomyopathy are associated with differences in TNF-receptor expression [J]. J Clin Invest,2000,106(4):589-597.
[311]Micheau O, Tschopp J. Induction of TNF receptor Ⅰ-mediated apoptosis via two sequential signaling complexes [J]. Cell,2003,114(2):181-190.
[312]Scheidereit C. IκB kinase complexes:gateways to NF-κB activation and transcription [J]. Oncogene,2006,25(51):6685-6705.
[313]Kleinbongard P, Schulz R, Heusch G. TNFa in myocardial ischemia/reperfusion, remodeling and heart failure [J]. Heart Fail Rev,2011,16(1):49-69.
[314]Dawn B, Guo Y, Rezazadeh A, Wang OL, Stein AB, Hunt G, Varma J, et al. Tumor necrosis factor-a does not modulate ischemia/reperfusion injury in naive myocardium but is essential for the development of late preconditioning [J]. J Mol Cell Cardiol,2004,37(1):51-61.
[315]Flaherty MP, Guo Y, Tiwari S, Rezazadeh A, Hunt G, Sanganalmath SK, Tang XL et al. The role of TNF-a receptors p55 and p75 in acute myocardial ischemia/reperfusion injury and late preconditioning [J]. J Mol Cell Cardiol,2008, 45(6):735-741.
[316]Takahashi M. High-mobility group box 1 protein (HMGB1) in ischaemic heart disease:beneficial or deleterious? [J]. Cardiovasc Res,2008,80(1):5-6.
[317]Goldstein RS, Gallowitsch-Puerta M, Yang L, Rosas-Ballina M, Huston JM, Czura CJ, Lee DC, et al. Elevated high-mobility group box 1 levels in patients with cerebral and myocardial ischemia [J]. Shock,2006,25(6):571-574.
[318]Tsung A, Sahai R, Tanaka H, Nakao A, Fink MP, Lotze MT, Yang H, et al. The nuclear factor HMGB1 mediates hepatic injury after murine liver ischemia-reperfusion [J]. J Exp Med,2005,201(7):1135-1143.
[319]Hu X, Zhou X, He B, Xu C, Wu L, Cui B, Wen H, et al. Minocycline protects against myocardial ischemia and reperfusion injury by inhibiting high mobility group box 1 protein in rats [J]. Eur J Pharmacol,2010,638(1-3):84-89.
[320]Abarbanell AM, Hartley JA, Herrmann JL, Weil BR, Wang Y, Manukyan MC, Poynter JA, et al. Exogenous high-mobility group box 1 improves myocardial recovery after acute global ischemia/reperfusion injury [J]. Surgery,2011, 149(3):329-335.
[321]Fukushima S, Coppen SR, Varela-Carver A, Yamahara K, Sarathchandra P, Smolenski RT, Yacoub MH, et al. A novel strategy for myocardial protection by combined antibody therapy inhibiting both P-selectin and intercellular adhesion molecule-1 via retrograde intracoronary route [J]. Circulation,2006,114(1 Suppl):I251-1256.
[322]Jones SP, Trocha SD, Strange MB, Granger DN, Kevil CG, Bullard DC, Lefer DJ. Leukocyte and endothelial cell adhesion molecules in a chronic murine model of myocardial reperfusion injury [J]. Am J Physiol Heart Circ Physiol,2000, 279(5):H2196-H2201.
[323]Palazzo AJ, Jones SP, Girod WG, Anderson DC, Granger DN, Lefer DJ. Myocardial ischemia-reperfusion injury in CD 18- and ICAM-1-deficient mice [J]. Am J Physiol,1998,275(6 Pt 2):H2300-H2307.
[324]Zitta K, Brandt B, Wuensch A, Meybohm P, Bein B, Steinfath M, Scholz J, et al. Interleukin-1β regulates cell proliferation and activity of extracellular matrix remodelling enzymes in cultured primary pig heart cells [J]. Biochem Biophys Res Commun,2010,399(4):542-547.
[325]Meybohm P, Gruenewald M, Albrecht M, Zacharowski KD, Lucius R, Zitta K, Koch A, et al. Hypothermia and postconditioning after cardiopulmonary resuscitation reduce cardiac dysfunction by modulating inflammation, apoptosis and remodeling [J]. PLoS One,2009,4(10):e7588.
[326]Matsushita K, Iwanaga S, Oda T, Kimura K, Shimada M, Sano M, Umezawa A, et al. Interleukin-6/soluble interleukin-6 receptor complex reduces infarct size via inhibiting myocardial apoptosis [J]. Lab Invest,2005,85(10):1210-1223.
[327]Frangogiannis NG, Mendoza LH, Lindsey ML, Ballantyne CM, Michael LH, Smith LH, Smith CW, Entman ML. IL-10 is induced in the reperfused myocardium and may modulate the reaction to injury [J]. J Immunol,2000,165(5):2798-2808.
[328]Tedgui A, Mallat Z. Anti-inflammatory mechanisms in the vascular wall [J]. Circ Res,2001,88(9):877-887.
[329]Hayward R, Nossuli TO, Scalia R, Lefer AM. Cardioprotective effect of interleukin-10 in murine myocardial ischemia-reperfusion [J]. Eur J Pharmacol, 1997,334(2-3):157-163.
[330]Dominguez-Rodriguez A, Abreu-Gonzalez P, de la Rosa A, Vargas M, Ferrer J, Garcia M. Role of endogenous interleukin-10 production and lipid peroxidation in patients with acute myocardial infarction treated with primary percutaneous transluminal coronary angioplasty, interleukin-10 and primary angioplasty [J]. Int J Cardiol,2005,99(1):77-81.
[331]Giomarelli P, Scolletta S, Borrelli E, Biagioli. Myocardial and lung injury after cardiopulmonary bypass:role of interleukin (IL)-10 [J]. Ann Thorac Surg,2003, 76(1):117-123.
[332]Dominguez RA, Abreu GP, Garcia GM, Ferrer HJ. Association between serum interleukin 10 level and development of heart failure in acute myocardial infarction patients treated by primary angioplasty [J]. Rev Esp Cardiol,2005,58(6):626-630.
[333]Zymek P, Nah DY, Bujak M, Ren G, Koerting A, Leucker T, Huebener P, et al. Interleukin-10 is not a critical regulator of infarct healing and left ventricular remodeling [J].2007,74(2):313-322.
[334]Friedman BH, Thayer JF. Anxiety and autonomic flexibility:a cardiovascular approach [J]. Biol Psychol,1998,49(3):303-323.
[335]Thayer JF, Lane RD. A model of neurovisceral integration in emotion regulation and dysregulation [J]. J Affect Disord,2000,61(3):201-216.
[336]Thayer JF, Lane RD. The role of vagal function in the risk for cardiovascular disease and mortality [J]. Biol Psychol,2007,74(2):224-242.
[337]Zamotrinsky AV, Kondratiev B, de Jong JW. Vagal neuro stimulation in patients with coronary artery disease [J]. Auton Neurosci,2001,88(1-2):109-116.
[338]Uijtdehaage SH, Thayer JF. Accentuated antagonism in the control of human heart rate [J]. Clin Auton Res,2000,10(3):107-110.
[339]Habib G. Reappraisal of the importance of heart rate as a risk factor for cardiovascular morbidity and mortality [J]. Clin Ther,1997,19 Suppl A:39-52.
[340][No authors listed] Heart rate variability:standards of measurement, physiological interpretation and clinical use. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology [J]. Circulation, 1996,93(5):1043-1065.
[341]Kiecolt-Glaser JK, McGuire L, Robles TF, Glaser R. Emotions, morbidity, and mortality:new perspectives from psychoneuroimmunology [J]. Annu Rev Psychol, 2002,53:83-107.
[342]Ershler WB, Keller ET. Age-associated increased interleukin-6 gene expression, late-life diseases, and frailty [J]. Annu Rev Med,2000,51:245-270.
[343]Blalock JE. The immune system as the sixth sense [J]. J Intern Med,2005, 257(2):126-138.
[344]Watkins LR, Maier SF. Implications of immune-to-brain communication for sickness and pain [J]. Proc Natl Acad Sci U S A,1999,96(14):7710-7713.
[345]Hansen MK, Nguyen KT, Goehler LE, Gaykema RP, Fleshner M, Maier SF, Watkins LR. Effects of vagotomy on lipopolysaccharide-induced brain interleukin-1β protein in rats [J]. Auton Neurosci,2000,85(1-3):119-126.
[346]Bernik TR, Friedman SG, Ochani M, Diraimo R, Uloa L, Yang H, Sudan S, et al. Pharmacological stimulation of the cholinergic antiinflammatory pathway [J]. J Exp Med,2002,195(6):781-788.
[347]Laye S, Parnet P, Goujon E, Dantzer R. Peripheral administration of lipopolysaccharide induces the expression of cytokine transcripts in the brain and pituitary of mice [J]. Brain Res Mol Brain Res,1994,27(1):157-162.
[348]Hosoi T, Okuma Y, Nomura Y. Electrical stimulation of afferent vagus nerve induces IL-1β expression in the brain and activates HPA axis [J]. Am J Physiol Regul Integr Comp Physiol,2000,279(1):R141-R147.
[349]Tracey KJ, Beutler B, Lowry SF, Merryweather J, Wolpe S, Milsark IW, Hariri RJ, et al. Shock and tissue injury induced by recombinant human cachectin [J]. Science, 1986,234(4775):470-474.
[350]Wang H, Bloom O, Zhang M, Vishnubhakat JM, Ombrellino M, Che J, Frazier A, et al. HMG-1 as a late mediator of endotoxin lethality in mice [J]. Science,1999, 285(5425):248-251.
[351]Dinarello CA. The interleukin-1 family:10 years of discovery [J]. FASEB J,1994, 8(15):1314-1325.
[352]Nathan CF. Secretory products of macrophages [J]. J Clin Invest,1987, 79(2):319-326.
[353]Kumins NH, Hunt J, Gamelli RL, Filkins JP. Partial hepatectomy reduces the endotoxin-induced peak circulating level of tumor necrosis factor in rats [J]. Shock, 1996,5(5):385-388.
[354]Gregory SH, Wing EJ. Neutrophil-Kupffer-cell interaction in host defenses to systemic infections [J]. Immunol Today,1998,19(11):507-510.
[355]van Westerloo DJ, Giebelen IA, Meijers JC, Daalhuisen J, de Vos AF, Levi M, van der Poll T. Vagus nerve stimulation inhibits activation of coagulation and fibrinolysis during endotoxemia in rats [J]. J Thromb Haemost,2006, 4(9):1997-2002.
[356]Wang H, Yu M, Ochani M, Amella CA, Tanovic M, Susarla S, Li JH, et al. Nicotinic acetylcholine receptor α 7 subunit is an essential regulator of inflammation [J]. Nature,2003,421(6921):384-388.
[357]Das UN. Can vagus nerve stimulation halt or ameliorate rheumatoid arthritis and lupus? [J]. Lipids Health Dis,2011,10:19.
[358]Bruchfeld A, Goldstein RS, Chavan S, Patel NB, Rosas-Ballina M, Kohn N, Qureshi AR, et al. Whole blood cytokine attenuation by cholinergic agonists ex vivo and relationship to vagus nerve activity in rheumatoid arthritis [J]. J Intern Med,2010,268(1):94-101.
[359]Taylor CT, Keely SJ. The autonomic nervous system and inflammatory bowel disease [J]. Auton Neurosci,2007,133(1):104-114.
[360]Singh V, Devgan L, Bhat S, Milner SM. The pathogenesis of burn wound conversion [J]. Ann Plast Surg,2007,59(1):109-115.
[361]Song XM, Li JG, Wang YL, Liang H, Huang Y, Yuan X, Zhou Q, et al. Effect of vagus nerve stimulation on thermal injury in rats [J]. Burns,2010,36(1):75-81.
[362]Maass DL, White J, Horton JW. IL-1β and IL-6 act synergistically with TNF-a to alter cardiac contractile function after burn trauma [J]. Shock,2002,18(4):360-366.
[363]Niederbichler AD, Papst S, Claassen L, Jokuszies A, Steinstraesser L, Hirsch T, Altintas MA, et al. Burn-induced organ dysfunction:vagus nerve stimulation attenuates organ and serum cytokine levels [J]. Burns,2009,35(6):783-789.
[364]Kumar V, Sharma A. Is neuroimmunomodulation a future therapeutic approach for sepsis? [J]. Int Immunopharmacol,2010,10(1):9-17.
[365]van Westerloo DJ, Giebelen IA, Florquin S, Daalhuisen J, Bruno MJ, de Vos AF, Tracey KJ, et al. The cholinergic anti-inflammatory pathway regulates the host response during septic peritonitis [J]. J Infect Dis,2005,191(12):2138-2148.
[366]Boland C, Collet V, Laterre E, Lecuivre C, Wittebole X, Laterre PF. Electrical vagus nerve stimulation and nicotine effects in peritonitis-induced acute lung injury in rats [J]. Inflammation,2011,34(1):29-35.
[367]Song XM, Li JG, Wang YL, Hu ZF, Zhou Q, Du ZH, Jia BH. The protective effect of the cholinergic anti-inflammatory pathway against septic shock in rats [J]. Shock, 2008,30(4):468-472.
[368]Huston JM, Gallowitsch-Puerta M, Ochani M, Ochani K, Yuan R, Rosas-Ballina M, Ashok M, et al. Transcutaneous vagus nerve stimulation reduces serum high mobility group box 1 levels and improves survival in murine sepsis [J]. Crit Care Med,2007,35(12):2762-2768.
[369]Lubbers T, Buurman W, Luyer M. Controlling postoperative ileus by vagal activation [J]. World J Gastroenterol,2010,16(14):1683-1687.
[370]Lubbers T, Luyer MD, de Haan JJ, Hadfoune M, Buurman WA, Greve JW. Lipid-rich enteral nutrition reduces postoperative ileus in rats via activation of cholecystokinin-receptors [J]. Ann Surg,2009,249(3):481-487.
[371]de Jonge WJ, The FO, van der Coelen D, Bennink RJ, Reitsma PH, van Deventer SJ, van den Wijingaard RM, et al. Mast cell degranulation during abdominal surgery initiates postoperative ileus in mice [J]. Gastroenterology,2004, 127(2):535-545.
[372]The FO, Bennink RJ, Ankum WM, Buist MR, Busch OR, Gouma DJ, van der Heide S, et al. Intestinal handling-induced mast cell activation and inflammation in human postoperative ileus [J]. Gut,2008,57(1):33-40.
[373]Kalff JC, Schraut WH, Billiar TR, Simmons RL, Bauer AJ. Role of inducible nitric oxide synthase in postoperative intestinal smooth muscle dysfunction in rodents [J]. Gastroenterology,2000,118(2):316-327.
[374]Schwarz NT, Kalff JC, Turler A, Engel BM, Watkins SC, Billiar TR, Bauer AJ. Prostanoid production via COX-2 as a causative mechanism of rodent postoperative ileus [J]. Gastroenterology,2001,121(6):1354-1371.
[375]The FO, Boeckxstaens GE, Snoek SA, Cash JL, Bennink R, Larosa GJ, van den Wijingaard RM, et al. Activation of the cholinergic anti-inflammatory pathway ameliorates postoperative ileus in mice [J]. Gastroenterology,2007, 133(4):1219-1228.
[376]De Herdt V, Bogaert S, Bracke KR, Raedt R, De Vos M, Vonck K, Boon P. Effects of vagus nerve stimulation on pro-and anti-inflammatory cytokine induction in patients with refractory epilepsy [J]. J Neuroimmunol,2009,214(1-2):104-108.
[377]Guarini S, Altavilla D, Cainazzo MM, Giuliani D, Bigiani A, Marini H, Squadrito G, et al. Efferent vagal fibre stimulation blunts nuclear factor-κB activation and protects against hypovolemic hemorrhagic shock [J]. Circulation,2003, 107(8):1189-1194.
[378]Altavilla D, Saitta A, Guarini S, Galeano M, Squadrito G, Cucinotta D, Santamaria LB, et al. Oxidative stress causes nuclear factor-κB activation in acute hypovolemic hemorrhagic shock [J]. Free Radic Biol Med,2001,30(10):1055-1066.
[379]Shahani R, Marshall JG, Rubin BB, Li RK, Walker PM, Lindsy TF. Role of TNF-a in myocardial dysfunction after hemorrhagic shock and lower-torso ischemia [J]. Am J Physiol Heart Circ Physiol,2000,278(3):H942-H950.
[380]Li W, Olshansky B. Inflammatory cytokines and nitric oxide in heart failure and potential modulation by vagus nerve stimulation [J]. Heart Fail Rev,2011, 16(2):137-145.
[381]Yellon DM, Baxter GF. Protecting the ischaemic and reperfused myocardium in acute myocardial infarction:distant dream or near reality? [J]. Heart,2000, 83(4):381-387.
[382]Piper HM, Abdallah Y, Schafer C. The first minutes of reperfusion:a window of opportunity for cardioprotection [J]. Cardiovasc Res,2004,61(3):365-371.
[383]Ezekowitz JA, Kaul P, Bakal JA, Armstrong PW, Welsh RC, Mcalister FA. Declining in-hospital mortality and increasing heart failure incidence in elderly patients with first myocardial infarction [J]. J Am Coll Cardiol,2009,53(1):13-20.
[384]Shanmuganathan S, Hausenloy DJ, Duchen MR, Yellon DM. Mitochondrial permeability transition pore as a target for cardioprotection in the human heart [J]. Am J Physiol Heart Circ Physiol,2005,289(1):H237-H242.
[385]Loffelholz K, Pappano AJ. The parasympathetic neuroeffector junction of the heart [J]. Pharmacol Rev,1985,37(1):1-24.
[386]Rardon DP, Bailey JC. Parasympathetic effects on electrophysiologic properties of cardiac ventricular tissue [J]. J Am Coll Cardiol,1983,2(6):1200-1209.
[387]Amlie JP, Refsum H. Vagus-induced changes in ventricular electrophysiology of the dog heart with and without β-blockade [J]. J Cardiovasc Pharmacol,1981, 3(6):1203-1210.
[388]Kawada T, Yamazaki T, Akiyama T, Li M, Ariumi H, Mori H, Sunagawa K, et al. Vagal stimulation suppresses ischemia-induced myocardial interstitial norepinephrine release [J]. Life Sci,2006,78(8):882-887.
[389]Schomig A, Fischer S, Kurz T, Richardt G, Schomig E. Nonexocytotic release of endogenous noradrenaline in the ischemic and anoxic rat heart:mechanism and metabolic requirements [J]. Circ Res,1987,60(2):194-205.
[390]Bazzani C, Guarini S, Botticelli AR, Zaffe D, Tomasi A, Bini A, Cainazzo MM, et al. Protective effect of melanocortin peptides in rat myocardial ischemia [J]. J Pharmacol Exp Ther,2001,297(3):1082-1087.
[391]O'Neill CA, Fu L W, Halliwell B, Longhurst JC. Hydroxyl radical production during myocardial ischemia and reperfusion in cats [J]. Am J Physiol,1996,271(2 Pt 2):H660-H667.
[392]Bolli R, Marban E. Molecular and cellular mechanisms of myocardial stunning [J]. Physiol Rev,1999,79(2):609-634.
[393]Ramasamy R, Hwang YC, Liu Y, Son NH, Ma N, Parkinson J, Sciaccca R, et al. Metabolic and functional protection by selective inhibition of nitric oxide synthase 2 during ischemia-reperfusion in isolated perfused hearts [J]. Circulation,2004, 109(13):1668-1673.
[394]Mioni C, Giuliani D, Cainazzo MM, Leone S, Bazzani C, Grieco P, Novellino E, et al. Further evidence that melanocortins prevent myocardial reperfusion injury by activating melanocortin MC3 receptors [J]. Eur J Pharmacol,2003,477(3):227-234.
[395]Rardon DP, Bailey JC. Direct effects of cholinergic stimulation on ventricular automaticity in guinea pig myocardium [J]. Circ Res,1983,52(1):105-110.
[396]Hashimoto K, Moe GK. Transient depolarizations induced by acetylstrophanthidin in specialized tissue of dog atrium and ventricle [J]. Circ Res,1973,32(5):618-624.
[397]Sammel NL, Norris RM, Hughes CF, Johnson RN, Ashton NG, Elliott RL. Severity of canine myocardial infarcts in relation to indices of oxygen demand: preservation of myocardial creatine kinase activity by vagal stimulation and propranolol [J]. Cardiovasc Res,1983,17(1):50-60.
[398]Shinke T, Takeuchi M, Takaoka H, Yokoyama M. Beneficial effects of heart rate reduction on cardiac mechanics and energetics in patients with left ventricular dysfunction [J]. Jpn Circ J,1999,63(12):957-964.
[399]Maughan WL, Sunagawa K, Burkhoff D, Graves WL Jr, Hunter WC, Sagawa K. Effect of heart rate on the canine end-systolic pressure-volume relationship [J]. Circulation,1985,72(3):654-659.
[400]Buck JD, Warltier DC, Hardman HF, Gross GJ. Effects of sotalol and vagal stimulation on ischemic myocardial blood flow distribution in the canine heart [J]. J Pharmacol Exp Ther,1981,216(2):347-351.
[401]Feigl EO. Parasympathetic control of coronary blood flow in dogs [J]. Circ Res, 1969,25(5):509-519.
[402]Reid JV, Ito BR, Huang AH, Buffington CW, Feigl EO. Parasympathetic control of transmural coronary blood flow in dogs [J]. Am J Physiol,1985,249(2 Pt 2):H337-H343.
[403]Feliciano L, Henning RJ. Vagal nerve stimulation releases vasoactive intestinal peptide which significantly increases coronary artery blood flow [J]. Cardiovasc Res,1998,40(1):45-55.
[404]Henning RJ, Sawmiller DR. Vasoactive intestinal peptide:cardiovascular effects [J]. Cardiovasc Res,2001,49(1):27-37.
[405]Schachter SC. Vagus nerve stimulation therapy summary:five years after FDA approval [J]. Neurology,2002,59(6 Suppl 4):S15-S20.
[406]Uthman BM, Reichl AM, Dean JC, Eisenschenk S, Gilmore R, Reid S, Roper SN, et al. Effectiveness of vagus nerve stimulation in epilepsy patients:a 12-year observation [J]. Neurology,2004,63(6):1124-1126.
[407]Nemeroff CB, Mayberg HS, Krahl SE, Mcnamara J, Frazer A, Henry TR, George MS, et al. VNS therapy in treatment-resistant depression:clinical evidence and putative neurobiological mechanisms [J]. Neuropsychopharmacology,2006, 31(7):1345-1355.
[408]Vanoli E, De Ferrari GM, Stramba-Badiale M, Hull SS Jr, Foreman RD, Schwartz PJ. Vagal stimulation and prevention of sudden death in conscious dogs with a healed myocardial infarction [J]. Circ Res,1991,68(5):1471-1481.
[409]Li M, Zheng C, Sato T, Kawada T, Sugimachi M, Sunagawa K. Vagal nerve stimulation markedly improves long-term survival after chronic heart failure in rats [J]. Circulation,2004,109(1):120-124.
[410]Vinten-Johansen J, Zhao ZQ, Jiang R, Zatta AJ, Dobson GP. Preconditioning and postconditioning:innate cardioprotection from ischemia-reperfusion injury [J]. J Appl Physiol,2007,103(4):1441-1448.
[411]De Ferrari GM, Vanoli E, Stramba-Badiale M, Hull SS Jr, Foreman RD, Schwartz PJ. Vagal reflexes and survival during acute myocardial ischemia in conscious dogs with healed myocardial infarction [J]. Am J Physiol,1991,261(1 Pt 2):H63-H69.
[412]Vanoli E, De Ferrari GM, Stramba-Badiale M, Hull SS Jr, Foreman RD, Schwartz PJ. Vagal stimulation and prevention of sudden death in conscious dogs with a healed myocardial infarction [J]. Circ Res,1991,68(5):1471-1481.
[413]Olshansky B, Sabbah HN, Hauptman PJ, Colucci WS. Parasympathetic nervous system and heart failure:pathophysiology and potential implications for therapy [J]. Circulation,2008,118(8):863-871.
[414]Zamotrinsky A, Afanasiev S, Karpov RS, Cherniavsky A. Effects of electrostimulation of the vagus afferent endings in patients with coronary artery disease [J]. Coron Artery Dis,1997,8(8-9):551-557.
[415]Tordoir JH, Scheffers I, Schmidli J, Savolainen H, Liebeskind U, Hansky B, Herold U, et al. An implantable carotid sinus baroreflex activating system:surgical technique and short-term outcome from a multi-center feasibility trial for the treatment of resistant hypertension [J]. Eur J Vasc Endovasc Surg,2007, 33 (4):414-421.
[416]Schauerte P, Mischke K, Plisiene J, Waldmann M, Zarse M, Stellbrink C, Schimpf T, et al. Catheter stimulation of cardiac parasympathetic nerves in humans:a novel approach to the cardiac autonomic nervous system [J]. Circulation,2001, 104(20):2430-2435.
[417]Dietrich S, Smith J, Scherzinger C, Hofmann-Preiss K, Freitag T, Eisenkolb A, Ringler R. A novel transcutaneous vagus nerve stimulation leads to brainstem and cerebral activations measured by functional MRI [J]. Biomed Tech (Berl),2008, 53(3):104-111.
[418]Kraus T, Hosl K, Kiess O, Schanze A, Kornhuber J, Forster C. BOLD fMRI deactivation of limbic and temporal brain structures and mood enhancing effect by transcutaneous vagus nerve stimulation [J]. J Neural Transm,2007, 114(11):1485-1493.
[419]Ventureyra EC. Transcutaneous vagus nerve stimulation for partial onset seizure therapy. A new concept [J]. Childs Nerv Syst,2000,16(2):101-102.
[420]Boon P, D'Have M, Van Walleghem P, Michielsen G, Vonck K, Caemaert J, De Reuck J. Direct medical costs of refractory epilepsy incurred by three different treatment modalities:a prospective assessment [J]. Epilepsia,2002,43(1):96-102.
[421]Ben-Menachem E, Hellstrom K, Verstappen D. Analysis of direct hospital costs before and 18 months after treatment with vagus nerve stimulation therapy in 43 patients [J]. Neurology,2002,59(6 Suppl 4):S44-S47.
[422]Forbes RB, Macdonald S, Eljamel S, Roberts RC. Cost-utility analysis of vagus nerve stimulators for adults with medically refractory epilepsy [J]. Seizure,2003, 12(5):249-256.
[423]Forbes R. Cost-utility of vagus nerve stimulation (VNS) therapy for medically refractory epilepsy-an update [J]. Seizure,2008,17(4):387-388.