α7nAChR激动剂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
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摘要
背景
众多动物实验表明,在急性心肌缺血所致的最终心肌梗死面积中,大约50%是由缺血-再灌注损伤(ischemia reperfusion injury)所引起。虽然缺血预处理(ischemic precondition)是目前已知的最强大的心肌保护干预措施,但是由于其需要在心肌缺血发生前实施干预,显然这在急性心肌梗死的情况下是不可能的,所以其临床应用受到了极大的限制。虽然缺血后处理(ischemic postconditioning)成功地解决了缺血预处理所存在的干预时机选择问题,但是由于其与缺血预处理一样仍然依赖于有创操作,所以其仅可应用于接受冠状动脉介入治疗的患者或针对急性心肌缺血而实施的某些心脏手术中。另外,缺血后处理这一有创性操作本身也并非适用于所有的患者,并有导致病变冠状动脉破裂或粥样硬化斑块脱落等其他并发症的高风险。鉴于缺血预处理和缺血后处理的局限性,就临床应用而言,在心肌缺血发生后进行药物治疗以获得有效的心肌保护作用,即“药物后处理”(pharmacological postconditioning)则具有更大的临床实际意义。目前,药物预处理和药物后处理均已成为缺血预处理或缺血后处理的有效替代途径。药物后处理的主要优点是临床应用不受心肌缺血时间的限制、方法简便、不需要有创操作和费用低廉等。
心肌缺血-再灌注损伤实际上是一种炎症反应,主要表现为炎症细胞局部侵润和炎症细胞因子大量产生和释放。晚近研究发现,胆碱能抗炎通路通过迷走神经作用于α7烟碱型乙酰胆碱受体(a7 nicotinic acetylcholiner receptor, a7nAChR)能够抑制炎症细胞因子的产生和释放,恢复炎症反应平衡,并保护机体。研究证实,迷走神经刺激可降低炎症反应时肿瘤坏死因子-α(tumor necrosisi factorα, TNF-α)、白介素6(interleukin 6, IL-6)和高迁移率组蛋白1 (high mobility group box 1, HMGB1)等炎症细胞因子的组织和循环血液水平,而且迷走神经刺激亦可保护缺血-再灌注所致的心肌损伤。由于应用a7nAChR激动剂能够产生与迷走神经刺激相同的效应,所以作为无创、操作简单的一种药物后处理,a7nAChR激动剂可能具有潜在的临床应用前景。虽然目前已有研究证实a7nAChR激动剂对肾脏缺血-再灌注损伤具有保护作用,但是a7nAChR激动剂对心肌缺血-再灌注损伤的保护作用尚未得到充分研究。
联合不同干预措施以获得更好的心肌保护效果一直是心肌缺血-再灌注损伤领域重要的研究方向之一,而缺血后处理和a7nAChR激动剂后处理这两种具有临床应用价值的心肌保护干预措施的触发机制明显不同。有鉴于此,我们设计了这个随机对照实验,旨在观察缺血后处理和α7nAChR激动剂后处理的心肌保护效果,并试图证实联合应用两者是否能够获得协同性心肌保护作用。另外,本实验还试图确定α7nAChR激动剂后处理的最佳干预时间,并研究PI3K/Akt和JAK/STAT信号转导通路在联合应用缺血后处理和α7nAChR激动剂后处理心肌保护作用中的地位,以探讨其相互作用的内在机制。本实验共分为三部分：
第1部分：PNU282987后处理和缺血后处理对在体大鼠心肌缺血-再灌注损伤及其炎症反应影响的实验研究
第1部分实验的目的是采用大鼠在体心肌缺血-再灌注损伤模型比较性观察PNU282987后处理和缺血后处理的心肌保护效应,并验证两种干预措施在降低心肌梗死面积方面是否存在有协同性作用。
将60只成年雄性Sprague Dawley (SD)大鼠(体重290-320g)麻醉后随机分为六组：空白对照组(S组,n=10)；对照组(C组,n=10)；缺血预处理组(IPC组,n=10)；缺血后处理组(IPOC组,n=10); PNU282987后处理组(P组,n=10)和联合应用PNU282987后处理和缺血后处理组(PPOC组,n=10)。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30 min(阻断LAD)和再灌注180 min(开放LAD)的处理。C组不采用任何干预措施；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5 min的LAD阻断和5 min的LAD开放组成,总处理时间是30min; IPOC组在再灌注前进行3个循环的缺血后处理,每个循环是由10s的LAD开放和10s的LAD阻断组成,总处理的时间是1min; S组、C组、IPC组和IPOC组大鼠均在30 min缺血后腹腔注射生理盐水1.5ml。P组于再灌注前腹腔注射PNU282987 2.4mg/kg; PPOC组的处理同IPOC组,并于再灌注前腹腔注射PNU282987 2.4mg/kg。实验过程中,连续监测心率(heart rate, HR).平均动脉压(mean arterial presure, MAP)和Ⅱ导联心电图(ECG),并保持大鼠直肠温度在36.5-37.5℃之间。在再灌注30 min和180 mmin时抽取血标本,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)、TNF-α、IL-6和HMGB1浓度。随后采用伊文思蓝和氯化三苯基四氮唑双重染色检测心肌梗死面积(infarctsize, IS%)。
结果显示,各组大鼠的一般情况、心肌缺血前血流动力学参数的基础值和心肌缺血后15min的血流动力学参数比较差异均无显著统计学意义。
再灌注期间S组的心率血压乘积(rate-pressure product, RPP)显著高于C组。C组的MAP显著低于S组、IPC组、IPOC组、P组和PPOC组。与IPC组相比,C组、IPOC组、P组和PPOC组缺血期发生室性心律失常的大鼠数目显著增多,并且缺血期室性心律失常评分显著增高。与C组相比,IPOC组和PPOC组再灌注初期发生室性心律失常的大鼠数目显著减少,并且再灌注初期室性心律失常评分也显著降低。
与C组相比,IPC组、IPOC组、P组和PPOC组的IS%和血清cTnI浓度均显著降低；与IPC组相比,PPOC组的IS%无显著统计学差异,虽然IPOC组和P组的IS%显著增高,但P和PPOC组的TnI血清浓度显著降低；与IPOC组相比,P组的IS%无显著统计学差异,但PPOC组的IS%显著降低,并且P组和PPOC组的TnI显著降低。析因分析结果显示,PNU282987后处理和缺血后处理在降低IS%方面无交互作用。
与S组相比,C组再灌注30 min时血清TNF-a和IL-6浓度显著增高,再灌注180min时血清TNF-α、IL-6和HMGB1浓度也显著增高。与C组相比,IPC组、IPOC组、P组和PPOC组再灌注180 min时血清TNF-a和HMGB1浓度均显著降低；除IPOC组再灌注30 min时血清TNF-a和IL-6浓度显著增高之外,IPC组、P组和PPOC组再灌注30 min时血清TNF-a和IL-6浓度均显著降低；并且P组和PPOC组再灌注180 min时的血清IL-6浓度也显著降低,而IPOC组再灌注180 min时血清IL-6浓度显著增高。与IPC组相比,IPOC组再灌注30 min时血清TNF-a和IL-6浓度显著增高,再灌注180 min时血清TNF-a, IL-6和HMGB1浓度显著增高；P组再灌注30 min时血清TNF-a浓度以及再灌注180 min时血清TNF-a, IL-6和HMGB1浓度显著降低,但是再灌注30 min时IL-6血清浓度显著增高；PPOC组再灌注30 min时血清TNF-a和IL-6浓度以及再灌注180 min时血清IL-6和HMGB1浓度显著降低。与IPOC组相比,P组和IPOC组再灌注30 min时血清TNF-α和IL-6浓度以及再灌注180 min时的血清TNF-α, IL-6和HMGB1浓度也显著降低。
第2部分：PNU282987后处理减轻大鼠在体心肌缺血-再灌注损伤最佳干预时间的实验研究
根据第1部分的研究结果,我们设计了这部分实验,其目的是探讨在心肌缺血再灌注过程中何时实施PNU282987后处理能够获得最佳的心肌保护效应,以确定PNU282987后处理的最佳干预时间。
将70只成年雄性SD大鼠(体重290-320g)麻醉后随机分为七组：空白对照组(S组,n=10)；对照组(C组,n=10)；缺血预处理组(IPC组,n=10)；PNU282987后处理组(P组,n=10)；再灌注30 min时PNU282987后处理组(P30组,n=10)；再灌注60min时PNU282987后处理组(P60组,n=10)和再灌注90 min时PNU282987后处理组(P90组,n=10)。C组、IPC组和P组的处理同第1部分实验,P30组、P60组和P90组的基本处理与C组相同,但分别在再灌注30 min、60 min和90 min时腹腔注射PNU282987 2.4mg/kg实施药物后处理。各项检测项目同实验第一部分。但仅在再灌注180 min时采血检测血清炎症细胞因子浓度。
结果显示,各组大鼠的一般情况、心肌缺血前血流动力学参数的基础值和心肌缺血后15min的血流动力学参数比较差异均无显著统计学意义。再灌注期,C组的MAP显著低于S组、IPC组、P组、P30组和P60组。心肌缺血期,IPC组发生室性心律失常的大鼠数目较C组、P组、P30组、P60组和P90组显著减少,并且室性心律失常评分显著降低。与IPC组相比,C组、P30组、P60组和P90组再灌注初期室性心律失常评分显著增高。
与C组相比,IPC组、P组、P30组、P60组和P90组再灌注180 min时的血清cTnI浓度和IS%值均显著降低。与IPC组相比,P组、P30组、P60组和P90组再灌注180 min时的血清cTnI浓度均显著降低,但是P组、P30组、P60组和P90组的IS%值显著增高。与P30组相比,P90组的IS%值显著增高。
与S组相比,再灌注180 min时血清TNF-α、IL-6和HMGB1浓度在C组显著增高。与C组相比,再灌注180 min时血清TNF-a和HMGB1浓度在IPC组、P组、P30组、P60组和P90组显著降低,并且再灌注180 min时血清IL-6浓度在P组、P30组、P60组和P90组显著降低。与IPC组相比,再灌注180 min时血清IL-6和HMGB1浓度在P组、P30组、P60组和P90组显著降低,再灌注180 min时血清TNF-α浓度在P组显著降低,但再灌注180 min时血清TNF-α浓度在P30和P60组显著增高。与P组相比,P30组、P60组和P90组再灌注180 min时血清TNF-α和HMGB1浓度显著增高,但再灌注180 min时血清IL-6浓度显著降低。与P30组相比,P60组和P90组再灌注180 min时血清TNF-a和HMGB1浓度显著降低,但再灌注180 min时血清IL-6浓度显著增高。
第3部分PI3K/Akt和JAK/STAT信号转导通路在联合应用PNU282987后处理和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信号转导通路在联合应用PNU282987后处理和缺血后处理心肌保护作用机制中的地位。
25只成年雄性SD大鼠(体重290-320g)麻醉后随机分为五组：对照组(C组,n=5)；缺血预处理组(IPC组,n=5)；缺血后处理组(IPOC组,n=5); PNU282987后处理组(P组,n=5)、联合应用PNU282987后处理和缺血后处理组(PPOC组,n=5)。在开放LAD实施再灌注60min时结束实验,取大鼠左心室缺血区心肌标本。由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基因在心肌组织的表达情况,并通过免疫蛋白印迹分析(Western-blotting)技术观察心肌组织Akt和STAT3蛋白磷酸化情况。
Western-blotting结果显示,与C组相比,IPC组的p-Akt显著增强,同时IPOC组的p-Akt和P-STAT3显著增强。与IPC组相比,P组的p-Akt和P-STAT3显著减弱,同时PPOC组的P-STAT3也显著减弱。与IPOC组相比,P组的p-Akt和P-STAT3显著减弱,PPOC组的P-STAT3也显著减弱。RQ-PCR结果显示,IPC组STAT3基因表达较C组和P组显著增强,而且IPOC组的Akt基因表达较PPOC组显著增强。
结论
通过本实验,我们得出以下结论：
1.PNU282987后处理和缺血后处理对大鼠心肌缺血-再灌注损伤的保护作用不尽相同。在减小心肌梗死面积方面两者的作用基本相同,但缺血后处理可显著抑制再灌注初期室性心律失常的发生,而PNU282987后处理对再灌注初期室性心律失常则无明显抑制作用。
2.联合应用PNU282987后处理和缺血后处理能够获得增强的心肌保护作用,并且联合应用两种干预措施亦可弥补PNU282987后处理不能抑制再灌注初期室性心律失常的缺点。
3.缺血预处理、PNU282987后处理、缺血后处理以及联合应用PNU282987后处理和缺血后处理均可明显抑制心肌缺血-再灌注过程中的炎症反应,并且是以联合应用PNU282987后处理和缺血后处理时的炎症反应抑制作用最强。但是,缺血预处理、PNU282987后处理和缺血后处理的炎症抑制作用在方式和强度方面存在有一定的差异。
4.再灌注30 min时实施PNU282987后处理的心肌保护效果最佳。
5.缺血预处理和缺血后处理的心肌保护作用涉及PI3K/Akt和JAK/STAT信号转导通路激活,并且这两个信号转导通路也参与PNU282987后处理以及联合应用PNU282987后处理和缺血后处理的心肌保护作用,但不是主要机制。PNU282987的心肌保护作用机制可能与缺血预处理和缺血后处理不同。
Background
Many animal studies have shown that after acute myocardial infarction, the ischemia reperfusion injury (IRI) is responsible for up to 50%of the final infarct size. Although the ischemia preconditioning (IPC) remains the most powerful cardioprotective measure, but 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. Ischemia postconditioning (IPOC) can be triggered during the clinically applicable period of reperfusion. However, it has the similar limitation as the IPC, i.e. requirement of an invasive protocol. Thus, the IPOC can only be utilized in the patients undergoing percutaneous coronary intervention (PCI) or special surgery for acute myocardial ischemia. Meanwhile, operation at the "culprit coronary artery" can produce new lesion of vessel or plaque fragmentation, which increase the risk of complications. Due to the limitations of the IPC and IPOC, pharmacological postconditioning protocol may be of more clinically feasible, by which cardioprotective drugs can be administered after ischemia insult. Now pharmacological preconditioning and postconditioning have been improved to substitute the IPC and IPOC effectively. The merits of pharmacological postconditioning include no limitation of myocardial ischemia, low cost, noninvasive and convenience.
Endogenous inflammatory response is a key factor in myocardial IRI, characterized with the local infiltration of inflammatory cells and excessive production and release of cytokines. Recently, cholinergic anti-inflammatory pathway has been demonstrated, by which vagus nerve can inhibit production of cytokines to avoid excessive inflammatory response through the specificα7 subunit of the nicotinic acetylcholine receptor (a7nAChR). Studies have identified that vagus nerve stimulation can decrease blood and tissue levels of tumor necrosis factor a (TNF-a), interleukin 6 (IL-6) and high mobility group box 1 (HMGB1), providing a protection against myocardial IRI. Because a7nAChR agonists can produce same effects as vagus nerve stimulation, they are potential treatments for myocardial IRI as noninvasive and effective pharmacological postconditioning. Although the renoprotective effect of a7nAChR agonist has been identified, there has still been no study evaluating its cardioprotection.
Combining different interventions to obtain an augmented cardioprotection is always one of the most popular research focuses in the area of myocardial IRI. Because IPOC andα7nAChR agonist postconditioning might be triggered by different mechanisms, we designed this randomized, controlled animal experimental study. The aims of the present study were:1) to investigate cardioprotection of the IPOC and a7nAChR agonist postconditioning; 2) to determine whether there was the synergistic cardioprotection by a combination of IPOC and a7nAChR agonist postconditioning; 3) to verify the best implementation time of a7nAChR agonist postconditioning; 4) to assess roles of both PI3K/Akt and JAK/STAT signal pathways in the cardioprotection of combined a7nAChR agonist postconditioning and IPOC, in order to explore the inherent mechanism of the interaction betweenα7nAChR agonist postconditioning and IPOC. This study was divided into the three parts.
Part 1 Experimental study on cardioprotective and anti-inflammatory effects of PNU282987 postconditioning and ischemia postconditioning in rat with myocardial ischemia reperfusion injury in vivo
In this part experiment, an in vivo rat model of myocardial IRI was used to compare the cardioprotection of PNU282987 and ischemia postconditioning, and to identify whether there was synergistic infarct-sparing effect by combining the two treatments.
Sixty anesthetized male Sprague Dawley rats (weighed 290 to 320 g) were randomly divided equally into six groups (n=10 in each group):sham group (S group), control group (C group), ischemia preconditioning group (IPC group), ischemia postconditioning group (IPOC group), PNU282987 postconditioning group (P group)and combined PNU282987 postconditioning and ischemia postconditioning group (PPOC group). After left thoracotomy in all rats, a 6-0 silk 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 for 30 min followed by a 180-min reperfusion. In C group, no additional intervention was performed. In IPC group, rats underwent three consecutive 5-min LAD occlusion followed by a 5-min reperfusion, which was performed before a 30-min LAD ligation. In IPOC group, animals were subjected to three cycles of a 10-sec reperfusion followed by a 10-sec LAD reocclusion, which was executed immediately at the onset of a 180-min reperfusion. Furthermore, the rats in the sham, control and IPOC groups were injected intraperitoneally with 1.5 ml normal saline at the end of ischemia. PNU282987 (2.4 mg/kg) was injected intraperitoneally immediately before a 180-min reperfusion in P group. In PPOC group, rats received not only the same IPOC protocol as that of the IPOC group, but also the same PNU282987 injection as that of the P group. Throughout the experiment, heart rate (HR), mean arterial pressure (MAP), and a lead II electrocardiogram were continuously monitored. The rectal temperature was maintained at 36.5-37.5℃. Blood samples were taken at 30 min and 180 min of reperfusion for measuring serum concentrations of troponin I (Tnl), TNF-a, HMGB-1 and IL-6 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.
The results showed that rat's body weight, body temperature and baselines of HR, MAP and RPP did not differ among the seven groups (P>0.05). Also, HR, MAP and RPP did not differ among these groups after 15 min ischemia (P>0.05).
During the period of reperfusion, the rate-pressure product (RPP) was significantly higher in S group than in C group. Also, MAP was significantly lower in C group than in S, IPC, IPOC, P and PPOC groups. Compared to IPC group, the number of rats suffering ischemic arrhythmia and arrhythmia score were significantly increased in C, IPOC, P and PPOC groups. Comparing to C group, the number of rats suffering reperfusion ventricular arrhythmia and arrhythmia score were significantly decreased in IPOC and PPOC groups.
The IS%and serum concentration of cTnl were significantly higher in C group than in IPC, IPOC, P and PPOC groups. Compared to IPC group, the IS%was significantly increased in IPOC and P groups, but the serum concentration of cTnl was significantly decreased in P and PPOC groups. There was no difference in the IS%between the IPC and PPOC groups. Compared to IPOC group, the IS%was significantly reduced in PPOC group, and serum concentration of cTnl was significantly reduced in P and PPOC groups. There was no difference in the IS%between the IPOC and P groups. The results of Factorial design ANOVA showed that there was no synergistic effect when combining ischemic postconditioning and PNU282987 postconditioning.
Compared to S group, the serum concentrations of TNF-a and IL-6 at 30 min of reperfusion and TNF-a, HMGB1 and IL-6 at 180 min of reperfusion were significantly increased in C group. Compared to C group, the serum concentrations of TNF-a and HMGB1 at 180 min of reperfusion were significantly decreased in IPC, IPOC, P and PPOC groups. The serum concentrations of TNF-a and IL-6 at 30 min of reperfusion were significantly higher in IPOC group than in C group, but the serum levels of TNF-a and IL-6 at 30 min of reperfusion were significantly lower in IPC, P and PPOC groups than in C group. The serum concentration of IL-6 at 180 min of reperfusion was significantly higher in IPOC group than in C group, however, the serum concentration of IL-6 at 180 min of reperfusion was significantly reduced in P and PPOC groups compared to C group. Compared to IPC group, the serum concentrations of TNF-a and IL-6 at 30 min of reperfusion and TNF-a, IL-6 and HMGB1 at 180 min of reperfusion were significantly increased in IPOC group. The serum concentrations of TNF-a, IL-6 and HMGB1 at 180 min of reperfusion and TNF-a at 30 min of reperfusion were significantly decreased in P group comparing to IPC group. However, the serum concentration of IL-6 at 30 min of reperfusion was significantly increased in P group comparing to IPC group. The Serum concentrations of TNF-a and IL-6 at 30 min of reperfusion and IL-6 and HMGB1 at 180 min of reperfusion were significantly lower in PPOC group than in IPC group. Compared to IPOC group, the serum concentrations of TNF-a and IL-6 at 30 min of reperfusion and those of TNF-a, IL-6 and HMGB1 at 180 min of reperfusion were significantly lower in P and PPOC groups.
Part 2 The best time of PNU282987 postconditioning attenuating myocardial ischemia reperfusion injury in rats
Based on the results from the first part experiment, we designed this part experiment to identify what time PNU282987 postconditioning was implemented during period of myocardial ischemia reperfusion injury process can produce the best cardioprotection.
Seventy anesthetized male SD rats (weighed 290 to 320 g) were randomly allocated into the six groups (n=10 in each group):S group, C group, IPC group, P group, PNU282987 postconditioning at 30 min reperfusion group (P30 group), PNU282987 postconditioning at 60 min reperfusion group (P60 group) and PNU282987 postconditioning at 90 min reperfusion group (P90 group). The procedures of C, IPC and P groups were as same as those in the first part experiment. The treatments of P30, P60 and P90 groups were similar to that of P group, except PNU282987 were administrated intraperitoneally at 30 min,60 min and 90 min of reperfusion, respectively. All testing variables in this part were as same as those in the first part. However, the serum concentrations of inflammatory cytokines were assayed only at 180 min of reperfusion.
The results showed that rat's body weight, body temperature and baselines of HR, MAP and RPP did not differ among the seven groups (P>0.05). Also, HR, MAP and RPP after 15 min of ischemia did also not differ among six groups (P>0.05). During the period of reperfusion, MAP was significantly lower in C group than in S, IPC, P, P30 and P60 groups. During the period of ischemia, the number of rat suffering ventricular arrhythmias and the score of arrhythmia were significantly reduced in IPC group compared to C, P, P30, P60 and P90 groups. Compared to IPC group, moreover, the arrhythmia score at onset of reperfusion was significantly increased in C, P30, P60 and P90 groups.
Compared to C group, the serum concentration of cTnl at 180 min of reperfusion and IS%were significantly decreased in IPC, P, P30, P60 and P90 groups. The serum concentration of cTnI at 180 min of reperfusion was significantly lower in P, P30, P60 and P90 groups than in IPC group, but the IS%was significantly higher in P, P30, P60 and P90 groups than in IPC group. Compared to P30 group, the IS%was significantly increased in P90 group.
Compared to S group, serum concentrations of TNF-a, IL-6 and HMGB1 at 180 min of reperfusion were significantly increased in C group. Compared to C group, the serum levers of TNF-a and HMGB1 at 180 min of reperfusion were significantly decreased in IPC, P, P30, P60 and P90 groups, and the serum concentration of IL-6 at 180 min of reperfusion were also significantly decreased in P, P30, P60 and P90 groups. Compared to IPC group, the serum concentrations of HMGB 1 and IL-6 at 180 min of reperfusion were significantly reduced in P, P30, P60 and P90 groups. Although the serum concentration of TNF-a at 180 min of reperfusion was significantly lower in P group than in IPC group, serum concentration of TNF-a at 180 min of reperfusion was significantly higher in P30 and P60 groups than in IPC group. Compared to P group, the serum levels of TNF-a and HMGB1 at 180 min of reperfusion were significantly increased in P30, P60 and P90 groups, but the serum concentration of IL-6 at 180 min of reperfusion was significantly reduced in these groups. The serum concentrations of TNF-a and HMGB1 at 180 min of reperfusion were significantly lower in P60 and P90 groups than in P30 group, however, the serum concentrations of IL-6 at 180 min of reperfusion were significantly increased in P60 and P90 group compared to P30 group.
Part 3 Roles of the PI3K/Akt and JAK/STAT signal pathways in the cardioprotection of combined PNU282987 postconditioning and ischemia conditioning
The aims of this part experiment were to explore the modulating roles of PI3K/Akt and JAK/STAT signal pathways in cardioprotective effects of combined PNU282987 postconditioning and IPOC.
Twenty five anesthetized male SD rats (weighed 290 to 320 g) were randomly divided equally into five groups (n=5 in each group):control group, IPC group, IPOC group, PNU282987 postconditioning group and combined PNU282987 postconditioning and IPOC group. After 60 min of reperfusion, the myocardial tissues from the area at risk in the left ventricle 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 gene expression of Akt and STAT3 in all groups. Also, phosphorylated Akt and phosphorylated STAT3 in all samples were assessed by Western-blotting technique.
Compared to C group, p-Akt in IPC group, and p-STAT3 and p-Akt were significantly increased in IPOC group. P-Akt and p-STAT3 in P group, and p-STAT3 in PPOC group were significantly lower than those in IPC group. Compared to IPOC group, p-Akt and p-STAT3 in P group and p-STAT3 in PPOC group were significantly reduced.
The results of RQ-PCR demonstrated that the expression of STAT3 gene was significantly enhanced in IPC group compared to C and P groups. Also, the expression of Akt gene was significantly higher in IPOC group than in PPOC group.
Conclusion
Based on the results of all experiments, the following conclusions can be drawn:
1. Cardioprotections induced by PNU282987 postconditioning and IPOC are not same. Although there is no significant difference between the two groups'effects of infarct size-sparing, IPOC inhibits reperfusion arrhythmia more effectively than PNU292987 postconditioning.
2. Combination of PNU282987 postconditioning and IPOC can provide a stronger cardioprotection, evidenced by reduction of infarct size. Also, inability of PNU282987 postconditioning related to reperfusion arrhythmia is eliminated by their combination.
3. In the present study, IPC, IPOC, PNU282987 postconditioning and combination of IPOC and PNU282987 postconditioning can inhibit the inflammatory response induced by the myocardial ischemia reperfusion injury. Also, the inflammatory inhibitory effect is strongest when combining PNU282987 postconditioning and IPOC. In addition, the intensity and pattern of inhibiting inflammatory response are different among the IPC, IPOC and PNU282987 postconditioning.
4. Compared to PNU282987 postconditioning at the onset of reperfusion,60 min and 90 min of reperfusion, PNU282987 postconditioning at 30 min of reperfusion can produce the best cardioprotection.
5. Although the cardioprotection of the IPC and IPOC may be contributed to activation of both PI3K/Akt and JAK/STAT signal pathways, these signal pathways are not the critical roles in the cardioprotection induced by PNU282987 postconditioning or the conbination of PNU282987 postconditioning and IPOC. The mechanisms of PNU282987 postconditioning against myocardial ischemia reperfusion injury may be different from those of the IPC and IPOC.
众多动物实验表明,在急性心肌缺血所致的最终心肌梗死面积中,大约50%是由缺血-再灌注损伤(ischemia reperfusion injury)所引起。虽然缺血预处理(ischemic precondition)是目前已知的最强大的心肌保护干预措施,但是由于其需要在心肌缺血发生前实施干预,显然这在急性心肌梗死的情况下是不可能的,所以其临床应用受到了极大的限制。虽然缺血后处理(ischemic postconditioning)成功地解决了缺血预处理所存在的干预时机选择问题,但是由于其与缺血预处理一样仍然依赖于有创操作,所以其仅可应用于接受冠状动脉介入治疗的患者或针对急性心肌缺血而实施的某些心脏手术中。另外,缺血后处理这一有创性操作本身也并非适用于所有的患者,并有导致病变冠状动脉破裂或粥样硬化斑块脱落等其他并发症的高风险。鉴于缺血预处理和缺血后处理的局限性,就临床应用而言,在心肌缺血发生后进行药物治疗以获得有效的心肌保护作用,即“药物后处理”(pharmacological postconditioning)则具有更大的临床实际意义。目前,药物预处理和药物后处理均已成为缺血预处理或缺血后处理的有效替代途径。药物后处理的主要优点是临床应用不受心肌缺血时间的限制、方法简便、不需要有创操作和费用低廉等。
心肌缺血-再灌注损伤实际上是一种炎症反应,主要表现为炎症细胞局部侵润和炎症细胞因子大量产生和释放。晚近研究发现,胆碱能抗炎通路通过迷走神经作用于α7烟碱型乙酰胆碱受体(a7 nicotinic acetylcholiner receptor, a7nAChR)能够抑制炎症细胞因子的产生和释放,恢复炎症反应平衡,并保护机体。研究证实,迷走神经刺激可降低炎症反应时肿瘤坏死因子-α(tumor necrosisi factorα, TNF-α)、白介素6(interleukin 6, IL-6)和高迁移率组蛋白1 (high mobility group box 1, HMGB1)等炎症细胞因子的组织和循环血液水平,而且迷走神经刺激亦可保护缺血-再灌注所致的心肌损伤。由于应用a7nAChR激动剂能够产生与迷走神经刺激相同的效应,所以作为无创、操作简单的一种药物后处理,a7nAChR激动剂可能具有潜在的临床应用前景。虽然目前已有研究证实a7nAChR激动剂对肾脏缺血-再灌注损伤具有保护作用,但是a7nAChR激动剂对心肌缺血-再灌注损伤的保护作用尚未得到充分研究。
联合不同干预措施以获得更好的心肌保护效果一直是心肌缺血-再灌注损伤领域重要的研究方向之一,而缺血后处理和a7nAChR激动剂后处理这两种具有临床应用价值的心肌保护干预措施的触发机制明显不同。有鉴于此,我们设计了这个随机对照实验,旨在观察缺血后处理和α7nAChR激动剂后处理的心肌保护效果,并试图证实联合应用两者是否能够获得协同性心肌保护作用。另外,本实验还试图确定α7nAChR激动剂后处理的最佳干预时间,并研究PI3K/Akt和JAK/STAT信号转导通路在联合应用缺血后处理和α7nAChR激动剂后处理心肌保护作用中的地位,以探讨其相互作用的内在机制。本实验共分为三部分：
第1部分：PNU282987后处理和缺血后处理对在体大鼠心肌缺血-再灌注损伤及其炎症反应影响的实验研究
第1部分实验的目的是采用大鼠在体心肌缺血-再灌注损伤模型比较性观察PNU282987后处理和缺血后处理的心肌保护效应,并验证两种干预措施在降低心肌梗死面积方面是否存在有协同性作用。
将60只成年雄性Sprague Dawley (SD)大鼠(体重290-320g)麻醉后随机分为六组：空白对照组(S组,n=10)；对照组(C组,n=10)；缺血预处理组(IPC组,n=10)；缺血后处理组(IPOC组,n=10); PNU282987后处理组(P组,n=10)和联合应用PNU282987后处理和缺血后处理组(PPOC组,n=10)。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30 min(阻断LAD)和再灌注180 min(开放LAD)的处理。C组不采用任何干预措施；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5 min的LAD阻断和5 min的LAD开放组成,总处理时间是30min; IPOC组在再灌注前进行3个循环的缺血后处理,每个循环是由10s的LAD开放和10s的LAD阻断组成,总处理的时间是1min; S组、C组、IPC组和IPOC组大鼠均在30 min缺血后腹腔注射生理盐水1.5ml。P组于再灌注前腹腔注射PNU282987 2.4mg/kg; PPOC组的处理同IPOC组,并于再灌注前腹腔注射PNU282987 2.4mg/kg。实验过程中,连续监测心率(heart rate, HR).平均动脉压(mean arterial presure, MAP)和Ⅱ导联心电图(ECG),并保持大鼠直肠温度在36.5-37.5℃之间。在再灌注30 min和180 mmin时抽取血标本,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)、TNF-α、IL-6和HMGB1浓度。随后采用伊文思蓝和氯化三苯基四氮唑双重染色检测心肌梗死面积(infarctsize, IS%)。
结果显示,各组大鼠的一般情况、心肌缺血前血流动力学参数的基础值和心肌缺血后15min的血流动力学参数比较差异均无显著统计学意义。
再灌注期间S组的心率血压乘积(rate-pressure product, RPP)显著高于C组。C组的MAP显著低于S组、IPC组、IPOC组、P组和PPOC组。与IPC组相比,C组、IPOC组、P组和PPOC组缺血期发生室性心律失常的大鼠数目显著增多,并且缺血期室性心律失常评分显著增高。与C组相比,IPOC组和PPOC组再灌注初期发生室性心律失常的大鼠数目显著减少,并且再灌注初期室性心律失常评分也显著降低。
与C组相比,IPC组、IPOC组、P组和PPOC组的IS%和血清cTnI浓度均显著降低；与IPC组相比,PPOC组的IS%无显著统计学差异,虽然IPOC组和P组的IS%显著增高,但P和PPOC组的TnI血清浓度显著降低；与IPOC组相比,P组的IS%无显著统计学差异,但PPOC组的IS%显著降低,并且P组和PPOC组的TnI显著降低。析因分析结果显示,PNU282987后处理和缺血后处理在降低IS%方面无交互作用。
与S组相比,C组再灌注30 min时血清TNF-a和IL-6浓度显著增高,再灌注180min时血清TNF-α、IL-6和HMGB1浓度也显著增高。与C组相比,IPC组、IPOC组、P组和PPOC组再灌注180 min时血清TNF-a和HMGB1浓度均显著降低；除IPOC组再灌注30 min时血清TNF-a和IL-6浓度显著增高之外,IPC组、P组和PPOC组再灌注30 min时血清TNF-a和IL-6浓度均显著降低；并且P组和PPOC组再灌注180 min时的血清IL-6浓度也显著降低,而IPOC组再灌注180 min时血清IL-6浓度显著增高。与IPC组相比,IPOC组再灌注30 min时血清TNF-a和IL-6浓度显著增高,再灌注180 min时血清TNF-a, IL-6和HMGB1浓度显著增高；P组再灌注30 min时血清TNF-a浓度以及再灌注180 min时血清TNF-a, IL-6和HMGB1浓度显著降低,但是再灌注30 min时IL-6血清浓度显著增高；PPOC组再灌注30 min时血清TNF-a和IL-6浓度以及再灌注180 min时血清IL-6和HMGB1浓度显著降低。与IPOC组相比,P组和IPOC组再灌注30 min时血清TNF-α和IL-6浓度以及再灌注180 min时的血清TNF-α, IL-6和HMGB1浓度也显著降低。
第2部分：PNU282987后处理减轻大鼠在体心肌缺血-再灌注损伤最佳干预时间的实验研究
根据第1部分的研究结果,我们设计了这部分实验,其目的是探讨在心肌缺血再灌注过程中何时实施PNU282987后处理能够获得最佳的心肌保护效应,以确定PNU282987后处理的最佳干预时间。
将70只成年雄性SD大鼠(体重290-320g)麻醉后随机分为七组：空白对照组(S组,n=10)；对照组(C组,n=10)；缺血预处理组(IPC组,n=10)；PNU282987后处理组(P组,n=10)；再灌注30 min时PNU282987后处理组(P30组,n=10)；再灌注60min时PNU282987后处理组(P60组,n=10)和再灌注90 min时PNU282987后处理组(P90组,n=10)。C组、IPC组和P组的处理同第1部分实验,P30组、P60组和P90组的基本处理与C组相同,但分别在再灌注30 min、60 min和90 min时腹腔注射PNU282987 2.4mg/kg实施药物后处理。各项检测项目同实验第一部分。但仅在再灌注180 min时采血检测血清炎症细胞因子浓度。
结果显示,各组大鼠的一般情况、心肌缺血前血流动力学参数的基础值和心肌缺血后15min的血流动力学参数比较差异均无显著统计学意义。再灌注期,C组的MAP显著低于S组、IPC组、P组、P30组和P60组。心肌缺血期,IPC组发生室性心律失常的大鼠数目较C组、P组、P30组、P60组和P90组显著减少,并且室性心律失常评分显著降低。与IPC组相比,C组、P30组、P60组和P90组再灌注初期室性心律失常评分显著增高。
与C组相比,IPC组、P组、P30组、P60组和P90组再灌注180 min时的血清cTnI浓度和IS%值均显著降低。与IPC组相比,P组、P30组、P60组和P90组再灌注180 min时的血清cTnI浓度均显著降低,但是P组、P30组、P60组和P90组的IS%值显著增高。与P30组相比,P90组的IS%值显著增高。
与S组相比,再灌注180 min时血清TNF-α、IL-6和HMGB1浓度在C组显著增高。与C组相比,再灌注180 min时血清TNF-a和HMGB1浓度在IPC组、P组、P30组、P60组和P90组显著降低,并且再灌注180 min时血清IL-6浓度在P组、P30组、P60组和P90组显著降低。与IPC组相比,再灌注180 min时血清IL-6和HMGB1浓度在P组、P30组、P60组和P90组显著降低,再灌注180 min时血清TNF-α浓度在P组显著降低,但再灌注180 min时血清TNF-α浓度在P30和P60组显著增高。与P组相比,P30组、P60组和P90组再灌注180 min时血清TNF-α和HMGB1浓度显著增高,但再灌注180 min时血清IL-6浓度显著降低。与P30组相比,P60组和P90组再灌注180 min时血清TNF-a和HMGB1浓度显著降低,但再灌注180 min时血清IL-6浓度显著增高。
第3部分PI3K/Akt和JAK/STAT信号转导通路在联合应用PNU282987后处理和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信号转导通路在联合应用PNU282987后处理和缺血后处理心肌保护作用机制中的地位。
25只成年雄性SD大鼠(体重290-320g)麻醉后随机分为五组：对照组(C组,n=5)；缺血预处理组(IPC组,n=5)；缺血后处理组(IPOC组,n=5); PNU282987后处理组(P组,n=5)、联合应用PNU282987后处理和缺血后处理组(PPOC组,n=5)。在开放LAD实施再灌注60min时结束实验,取大鼠左心室缺血区心肌标本。由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基因在心肌组织的表达情况,并通过免疫蛋白印迹分析(Western-blotting)技术观察心肌组织Akt和STAT3蛋白磷酸化情况。
Western-blotting结果显示,与C组相比,IPC组的p-Akt显著增强,同时IPOC组的p-Akt和P-STAT3显著增强。与IPC组相比,P组的p-Akt和P-STAT3显著减弱,同时PPOC组的P-STAT3也显著减弱。与IPOC组相比,P组的p-Akt和P-STAT3显著减弱,PPOC组的P-STAT3也显著减弱。RQ-PCR结果显示,IPC组STAT3基因表达较C组和P组显著增强,而且IPOC组的Akt基因表达较PPOC组显著增强。
结论
通过本实验,我们得出以下结论：
1.PNU282987后处理和缺血后处理对大鼠心肌缺血-再灌注损伤的保护作用不尽相同。在减小心肌梗死面积方面两者的作用基本相同,但缺血后处理可显著抑制再灌注初期室性心律失常的发生,而PNU282987后处理对再灌注初期室性心律失常则无明显抑制作用。
2.联合应用PNU282987后处理和缺血后处理能够获得增强的心肌保护作用,并且联合应用两种干预措施亦可弥补PNU282987后处理不能抑制再灌注初期室性心律失常的缺点。
3.缺血预处理、PNU282987后处理、缺血后处理以及联合应用PNU282987后处理和缺血后处理均可明显抑制心肌缺血-再灌注过程中的炎症反应,并且是以联合应用PNU282987后处理和缺血后处理时的炎症反应抑制作用最强。但是,缺血预处理、PNU282987后处理和缺血后处理的炎症抑制作用在方式和强度方面存在有一定的差异。
4.再灌注30 min时实施PNU282987后处理的心肌保护效果最佳。
5.缺血预处理和缺血后处理的心肌保护作用涉及PI3K/Akt和JAK/STAT信号转导通路激活,并且这两个信号转导通路也参与PNU282987后处理以及联合应用PNU282987后处理和缺血后处理的心肌保护作用,但不是主要机制。PNU282987的心肌保护作用机制可能与缺血预处理和缺血后处理不同。
Background
Many animal studies have shown that after acute myocardial infarction, the ischemia reperfusion injury (IRI) is responsible for up to 50%of the final infarct size. Although the ischemia preconditioning (IPC) remains the most powerful cardioprotective measure, but 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. Ischemia postconditioning (IPOC) can be triggered during the clinically applicable period of reperfusion. However, it has the similar limitation as the IPC, i.e. requirement of an invasive protocol. Thus, the IPOC can only be utilized in the patients undergoing percutaneous coronary intervention (PCI) or special surgery for acute myocardial ischemia. Meanwhile, operation at the "culprit coronary artery" can produce new lesion of vessel or plaque fragmentation, which increase the risk of complications. Due to the limitations of the IPC and IPOC, pharmacological postconditioning protocol may be of more clinically feasible, by which cardioprotective drugs can be administered after ischemia insult. Now pharmacological preconditioning and postconditioning have been improved to substitute the IPC and IPOC effectively. The merits of pharmacological postconditioning include no limitation of myocardial ischemia, low cost, noninvasive and convenience.
Endogenous inflammatory response is a key factor in myocardial IRI, characterized with the local infiltration of inflammatory cells and excessive production and release of cytokines. Recently, cholinergic anti-inflammatory pathway has been demonstrated, by which vagus nerve can inhibit production of cytokines to avoid excessive inflammatory response through the specificα7 subunit of the nicotinic acetylcholine receptor (a7nAChR). Studies have identified that vagus nerve stimulation can decrease blood and tissue levels of tumor necrosis factor a (TNF-a), interleukin 6 (IL-6) and high mobility group box 1 (HMGB1), providing a protection against myocardial IRI. Because a7nAChR agonists can produce same effects as vagus nerve stimulation, they are potential treatments for myocardial IRI as noninvasive and effective pharmacological postconditioning. Although the renoprotective effect of a7nAChR agonist has been identified, there has still been no study evaluating its cardioprotection.
Combining different interventions to obtain an augmented cardioprotection is always one of the most popular research focuses in the area of myocardial IRI. Because IPOC andα7nAChR agonist postconditioning might be triggered by different mechanisms, we designed this randomized, controlled animal experimental study. The aims of the present study were:1) to investigate cardioprotection of the IPOC and a7nAChR agonist postconditioning; 2) to determine whether there was the synergistic cardioprotection by a combination of IPOC and a7nAChR agonist postconditioning; 3) to verify the best implementation time of a7nAChR agonist postconditioning; 4) to assess roles of both PI3K/Akt and JAK/STAT signal pathways in the cardioprotection of combined a7nAChR agonist postconditioning and IPOC, in order to explore the inherent mechanism of the interaction betweenα7nAChR agonist postconditioning and IPOC. This study was divided into the three parts.
Part 1 Experimental study on cardioprotective and anti-inflammatory effects of PNU282987 postconditioning and ischemia postconditioning in rat with myocardial ischemia reperfusion injury in vivo
In this part experiment, an in vivo rat model of myocardial IRI was used to compare the cardioprotection of PNU282987 and ischemia postconditioning, and to identify whether there was synergistic infarct-sparing effect by combining the two treatments.
Sixty anesthetized male Sprague Dawley rats (weighed 290 to 320 g) were randomly divided equally into six groups (n=10 in each group):sham group (S group), control group (C group), ischemia preconditioning group (IPC group), ischemia postconditioning group (IPOC group), PNU282987 postconditioning group (P group)and combined PNU282987 postconditioning and ischemia postconditioning group (PPOC group). After left thoracotomy in all rats, a 6-0 silk 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 for 30 min followed by a 180-min reperfusion. In C group, no additional intervention was performed. In IPC group, rats underwent three consecutive 5-min LAD occlusion followed by a 5-min reperfusion, which was performed before a 30-min LAD ligation. In IPOC group, animals were subjected to three cycles of a 10-sec reperfusion followed by a 10-sec LAD reocclusion, which was executed immediately at the onset of a 180-min reperfusion. Furthermore, the rats in the sham, control and IPOC groups were injected intraperitoneally with 1.5 ml normal saline at the end of ischemia. PNU282987 (2.4 mg/kg) was injected intraperitoneally immediately before a 180-min reperfusion in P group. In PPOC group, rats received not only the same IPOC protocol as that of the IPOC group, but also the same PNU282987 injection as that of the P group. Throughout the experiment, heart rate (HR), mean arterial pressure (MAP), and a lead II electrocardiogram were continuously monitored. The rectal temperature was maintained at 36.5-37.5℃. Blood samples were taken at 30 min and 180 min of reperfusion for measuring serum concentrations of troponin I (Tnl), TNF-a, HMGB-1 and IL-6 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.
The results showed that rat's body weight, body temperature and baselines of HR, MAP and RPP did not differ among the seven groups (P>0.05). Also, HR, MAP and RPP did not differ among these groups after 15 min ischemia (P>0.05).
During the period of reperfusion, the rate-pressure product (RPP) was significantly higher in S group than in C group. Also, MAP was significantly lower in C group than in S, IPC, IPOC, P and PPOC groups. Compared to IPC group, the number of rats suffering ischemic arrhythmia and arrhythmia score were significantly increased in C, IPOC, P and PPOC groups. Comparing to C group, the number of rats suffering reperfusion ventricular arrhythmia and arrhythmia score were significantly decreased in IPOC and PPOC groups.
The IS%and serum concentration of cTnl were significantly higher in C group than in IPC, IPOC, P and PPOC groups. Compared to IPC group, the IS%was significantly increased in IPOC and P groups, but the serum concentration of cTnl was significantly decreased in P and PPOC groups. There was no difference in the IS%between the IPC and PPOC groups. Compared to IPOC group, the IS%was significantly reduced in PPOC group, and serum concentration of cTnl was significantly reduced in P and PPOC groups. There was no difference in the IS%between the IPOC and P groups. The results of Factorial design ANOVA showed that there was no synergistic effect when combining ischemic postconditioning and PNU282987 postconditioning.
Compared to S group, the serum concentrations of TNF-a and IL-6 at 30 min of reperfusion and TNF-a, HMGB1 and IL-6 at 180 min of reperfusion were significantly increased in C group. Compared to C group, the serum concentrations of TNF-a and HMGB1 at 180 min of reperfusion were significantly decreased in IPC, IPOC, P and PPOC groups. The serum concentrations of TNF-a and IL-6 at 30 min of reperfusion were significantly higher in IPOC group than in C group, but the serum levels of TNF-a and IL-6 at 30 min of reperfusion were significantly lower in IPC, P and PPOC groups than in C group. The serum concentration of IL-6 at 180 min of reperfusion was significantly higher in IPOC group than in C group, however, the serum concentration of IL-6 at 180 min of reperfusion was significantly reduced in P and PPOC groups compared to C group. Compared to IPC group, the serum concentrations of TNF-a and IL-6 at 30 min of reperfusion and TNF-a, IL-6 and HMGB1 at 180 min of reperfusion were significantly increased in IPOC group. The serum concentrations of TNF-a, IL-6 and HMGB1 at 180 min of reperfusion and TNF-a at 30 min of reperfusion were significantly decreased in P group comparing to IPC group. However, the serum concentration of IL-6 at 30 min of reperfusion was significantly increased in P group comparing to IPC group. The Serum concentrations of TNF-a and IL-6 at 30 min of reperfusion and IL-6 and HMGB1 at 180 min of reperfusion were significantly lower in PPOC group than in IPC group. Compared to IPOC group, the serum concentrations of TNF-a and IL-6 at 30 min of reperfusion and those of TNF-a, IL-6 and HMGB1 at 180 min of reperfusion were significantly lower in P and PPOC groups.
Part 2 The best time of PNU282987 postconditioning attenuating myocardial ischemia reperfusion injury in rats
Based on the results from the first part experiment, we designed this part experiment to identify what time PNU282987 postconditioning was implemented during period of myocardial ischemia reperfusion injury process can produce the best cardioprotection.
Seventy anesthetized male SD rats (weighed 290 to 320 g) were randomly allocated into the six groups (n=10 in each group):S group, C group, IPC group, P group, PNU282987 postconditioning at 30 min reperfusion group (P30 group), PNU282987 postconditioning at 60 min reperfusion group (P60 group) and PNU282987 postconditioning at 90 min reperfusion group (P90 group). The procedures of C, IPC and P groups were as same as those in the first part experiment. The treatments of P30, P60 and P90 groups were similar to that of P group, except PNU282987 were administrated intraperitoneally at 30 min,60 min and 90 min of reperfusion, respectively. All testing variables in this part were as same as those in the first part. However, the serum concentrations of inflammatory cytokines were assayed only at 180 min of reperfusion.
The results showed that rat's body weight, body temperature and baselines of HR, MAP and RPP did not differ among the seven groups (P>0.05). Also, HR, MAP and RPP after 15 min of ischemia did also not differ among six groups (P>0.05). During the period of reperfusion, MAP was significantly lower in C group than in S, IPC, P, P30 and P60 groups. During the period of ischemia, the number of rat suffering ventricular arrhythmias and the score of arrhythmia were significantly reduced in IPC group compared to C, P, P30, P60 and P90 groups. Compared to IPC group, moreover, the arrhythmia score at onset of reperfusion was significantly increased in C, P30, P60 and P90 groups.
Compared to C group, the serum concentration of cTnl at 180 min of reperfusion and IS%were significantly decreased in IPC, P, P30, P60 and P90 groups. The serum concentration of cTnI at 180 min of reperfusion was significantly lower in P, P30, P60 and P90 groups than in IPC group, but the IS%was significantly higher in P, P30, P60 and P90 groups than in IPC group. Compared to P30 group, the IS%was significantly increased in P90 group.
Compared to S group, serum concentrations of TNF-a, IL-6 and HMGB1 at 180 min of reperfusion were significantly increased in C group. Compared to C group, the serum levers of TNF-a and HMGB1 at 180 min of reperfusion were significantly decreased in IPC, P, P30, P60 and P90 groups, and the serum concentration of IL-6 at 180 min of reperfusion were also significantly decreased in P, P30, P60 and P90 groups. Compared to IPC group, the serum concentrations of HMGB 1 and IL-6 at 180 min of reperfusion were significantly reduced in P, P30, P60 and P90 groups. Although the serum concentration of TNF-a at 180 min of reperfusion was significantly lower in P group than in IPC group, serum concentration of TNF-a at 180 min of reperfusion was significantly higher in P30 and P60 groups than in IPC group. Compared to P group, the serum levels of TNF-a and HMGB1 at 180 min of reperfusion were significantly increased in P30, P60 and P90 groups, but the serum concentration of IL-6 at 180 min of reperfusion was significantly reduced in these groups. The serum concentrations of TNF-a and HMGB1 at 180 min of reperfusion were significantly lower in P60 and P90 groups than in P30 group, however, the serum concentrations of IL-6 at 180 min of reperfusion were significantly increased in P60 and P90 group compared to P30 group.
Part 3 Roles of the PI3K/Akt and JAK/STAT signal pathways in the cardioprotection of combined PNU282987 postconditioning and ischemia conditioning
The aims of this part experiment were to explore the modulating roles of PI3K/Akt and JAK/STAT signal pathways in cardioprotective effects of combined PNU282987 postconditioning and IPOC.
Twenty five anesthetized male SD rats (weighed 290 to 320 g) were randomly divided equally into five groups (n=5 in each group):control group, IPC group, IPOC group, PNU282987 postconditioning group and combined PNU282987 postconditioning and IPOC group. After 60 min of reperfusion, the myocardial tissues from the area at risk in the left ventricle 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 gene expression of Akt and STAT3 in all groups. Also, phosphorylated Akt and phosphorylated STAT3 in all samples were assessed by Western-blotting technique.
Compared to C group, p-Akt in IPC group, and p-STAT3 and p-Akt were significantly increased in IPOC group. P-Akt and p-STAT3 in P group, and p-STAT3 in PPOC group were significantly lower than those in IPC group. Compared to IPOC group, p-Akt and p-STAT3 in P group and p-STAT3 in PPOC group were significantly reduced.
The results of RQ-PCR demonstrated that the expression of STAT3 gene was significantly enhanced in IPC group compared to C and P groups. Also, the expression of Akt gene was significantly higher in IPOC group than in PPOC group.
Conclusion
Based on the results of all experiments, the following conclusions can be drawn:
1. Cardioprotections induced by PNU282987 postconditioning and IPOC are not same. Although there is no significant difference between the two groups'effects of infarct size-sparing, IPOC inhibits reperfusion arrhythmia more effectively than PNU292987 postconditioning.
2. Combination of PNU282987 postconditioning and IPOC can provide a stronger cardioprotection, evidenced by reduction of infarct size. Also, inability of PNU282987 postconditioning related to reperfusion arrhythmia is eliminated by their combination.
3. In the present study, IPC, IPOC, PNU282987 postconditioning and combination of IPOC and PNU282987 postconditioning can inhibit the inflammatory response induced by the myocardial ischemia reperfusion injury. Also, the inflammatory inhibitory effect is strongest when combining PNU282987 postconditioning and IPOC. In addition, the intensity and pattern of inhibiting inflammatory response are different among the IPC, IPOC and PNU282987 postconditioning.
4. Compared to PNU282987 postconditioning at the onset of reperfusion,60 min and 90 min of reperfusion, PNU282987 postconditioning at 30 min of reperfusion can produce the best cardioprotection.
5. Although the cardioprotection of the IPC and IPOC may be contributed to activation of both PI3K/Akt and JAK/STAT signal pathways, these signal pathways are not the critical roles in the cardioprotection induced by PNU282987 postconditioning or the conbination of PNU282987 postconditioning and IPOC. The mechanisms of PNU282987 postconditioning against myocardial ischemia reperfusion injury may be different from those of the IPC and IPOC.
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