联合应用肢体远隔缺血后处理和七氟烷后处理对大鼠心肌缺血再灌注损伤的保护作用及其机制的实验研究
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摘要
缺血再灌注损伤(ischemia reperfusion injury)的概念是在1960年由等Jennings首次提出,此后该问题成为了困扰医学工作者的一个难题。为了减轻心肌缺血再灌注损伤并最终缩小心肌梗死面积,在临床上和实验研究中均采取了多种干预措施。其中缺血预处理(ischemia preconditioning)强大的心肌保护作用已得到公认,但临床缺血事件的不可预测性使其更多地是停留在了理论层面。除了短暂缺血之外,多种刺激均可诱发缺血预处理样保护作用。吸入麻醉药七氟烷后处理的心肌保护作用已经在动物和人体研究中得到了证实,七氟烷后处理的主要优点是操作简单和实施容易,并且能够与其他多种心肌保护干预措施联合应用,对于减轻心肌缺血再灌注损伤是一种极具临床应用前景的干预措施。肢体远隔缺血后处理(limb remote ischemic postconditioning)是通过在上肢或下肢等部位实施远隔缺血刺激,以保护心肌对抗缺血再灌注损伤。肢体远隔缺血后处理的主要优点是实施简单、无需有创操作和不需要额外的费用,具有广阔的临床应用前景。
低氧诱导因子1(hypoxia-inducible factor1, HIF-1)能够在转录水平调节多种基因的表达,在细胞和组织缺血适应过程中发挥着至关重要的作用。其下游基因血红素氧化酶1(Heme oxygenase1, HO-1)和诱生型一氧化氮合酶(inducible nitric oxide synthase, iNOS)具有保护心肌对抗缺血再灌注损伤的作用。丝氨酸／苏氨酸激酶Akt和细胞外调节蛋白激酶(extracellular regulated protein kinases, ERK1/2)是再灌注损伤救援激酶途径(reperfusion injury salvage kinase pathway, RISK途径)的重要组成成分,是各种不同干预措施发挥心肌保护作用的交汇点。在缺血再灌注过程中, RISK途径激活能够对心肌损伤产生强大的保护作用。
本实验从临床应用出发,拟观察联合应用两种极具应用前景的干预措施—七氟烷后处理和肢体远隔缺血后处理能否获得有益的协同性心肌保护作用。同时对缺血缺氧过程中关键转录因子HIF-1的表达情况以及RISK途径的激活情况进行观察,以初步探讨这两种干预措施发挥作用的机制。全部实验共分三个部分：
第一部分：联合应用肢体远隔缺血后处理和七氟烷后处理组处理对心肌缺血再灌注损伤的保护作用
采用8周龄、体重250-320g的健康Sprague Dawley (SD)大鼠建立在体心肌缺血再灌注损伤模型,共分六个实验组(每组10只大鼠)：空白对照组(CON组)、缺血再灌注损伤组(IR组)、缺血预处理组(IPC组)、肢体远隔缺血后处理组(LRIPOC组)、七氟烷后处理组(SEVPOC组)以及联合应用肢体远隔缺血后处理和七氟烷后处理组(COMBINE组)。所有大鼠开胸后采用5-0丝线将冠状动脉左前降支(left anterior descending coronary artery, LAD)套扎做成活结。除CON组之外,所有大鼠均接受阻断LAD局部心肌缺血30min和开放LAD心肌血流再灌注120min的处理。IR组不采取任何其他措施；IPC组结扎LAD前进行3个循环(每个循环为5min缺血-5min再灌注)的缺血预处理,总处理时间为30min；LRIPOC组在心肌缺血15min时采用止血带结扎大鼠双侧后肢造成缺血10min,并在再灌注前5min开放后肢血流灌注；SEVPOC组在开放LAD实施再灌注前5min经小动物麻醉机的挥发罐吸入1MAC的七氟烷,直至再灌注后5min；COMBINE组在心肌缺血15min时采用止血带结扎大鼠双侧后肢造成肢体缺血10min,再灌注前5min开放后肢血流灌注,并吸入1MAC的七氟烷,直至再灌注后5min。实验过程中维持大鼠直肠体温在37-38℃范围内,连续监测心率(heart rate, HR)、收缩压(systolic blood pressure, SBP)、舒张压(diastolic blood pressure, DBP)、平均动脉压(mean arterial pressure, MAP)和Ⅱ导联ECG,并计算HR和SBP的乘积(rate-pressure product, RPP)作为心肌氧耗指数。记录实验中心律失常情况并进行评分。在再灌注120min时抽取动脉血标本,采用ELISA试剂盒检测大鼠血清乳酸脱氢酶(lactic dehydrogenase, LDH)、肌酸激酶心肌型同工酶(creatine kinase MB isoenzyme, CK-MB)和心肌肌钙蛋白I(cardiac Troponin-Ⅰ, cTnⅠ),并采用伊文思蓝和氯化三苯基四氮唑(TTC)双重染色测定梗死面积(infarct size, IS%)。
排除实验中不合格的大鼠,最终共有49只大鼠纳入实验,其中CON组9只,IR组、LRIPOC组、SEVPOC组、COMBINE组个IPC组各8只。各组大鼠的一般情况、缺血面积占左心室比值各组间比较差异均无统计学意义。
与IR组相比,LRIPOC组、SEVPOC组和COMBINE组再灌注初期发生心律失常的动物数有所减少和心律失常的持续时间有不同程度的缩短,但是差异无统计学意义。与IPC组相比,IR组、LRIPOC组、SEVPOC组和COMBINE组再灌注初期发生心律失常的动物数显著增多,心律失常持续时间和心律失常评分明显升高。
血清LDH浓度的总体组间比较差异有显著统计学意义(F=51.503,P<0.01)。与CON组相比,IR组、LRIPOC组、SEVPOC组、COMBINE组和IPC组血清LDH浓度明显升高；与IR组相比,LRIPOC组、SEVPOC组、COMBINE组和IPC组血清LDH浓度明显降低；与IPC组相比,COMBINE组血清LDH浓度无显著统计学差异,但LRIPOC组和SEVPOC组血清LDH浓度明显升高；LRIPOC组和SEVPOC组血清LDH浓度比较差异无显著统计学意义；与COMBINE组相比,LRIPOC组和SEVPOC组血清LDH浓度明显升高。
血清CK-MB浓度的总体组间比较差异有显著统计学意义(F=32.244,P<0.01)。与CON组相比,血清CK-MB浓度在IPC组和COMBINE组无显著统计学差异,在IR组、LRIPOC组和SEVPOC组明显升高；与IR组相比,LRIPOC组、SEVPOC组、COMBINE组和IPC组血清CK-MB浓度明显降低；与IPC组相比,LRIPOC组和SEVPOC组血清CK-MB浓度的明显升高；与COMBINE组相比,LRIPOC组和SEVPOC组血清CK-MB浓度无显著统计学差异。
血清cTnI浓度的总体组间比较差异有显著统计学意义(F=81.511,P<0.01)。与CON组相比,IR组、LRIPOC组、SEVPOC组、COMBINE组和IPC组血清cTnl浓度明显升高；与IR组相比,LRIPOC组、SEVPOC组、COMBINE组和IPC组血清cTnI浓度明显降低；与IPC组相比,血清cTnI浓度在COMBINE组无显著统计学差异,在LRIPOC组和SEVPOC组明显升高；LRIPOC组和SEVPOC组血清cTnI浓度比较差异无显著统计学意义；与COMBINE组相比,LRIPOC组和SEVPOC组血清cTnI浓度明显升高。
各组的心肌梗死面积(IS%值)为：CON组,(3.7±3.4)%；IR组,(64.2±13.6))%：LRIPOC组,(45.8±15.6)%；SEVPOC组,(43.6±9.7)%；COMBINE组,(30.9±11.3)%；IPC组,(22.0±5.0)%。IS%值的总体组间比较差异具有显著统计学意义(F=33.333,P<0.01)。心肌梗死面积两组之间的比较结果如下：与CON组相比,IR组、LRIPOC组、SEVPOC组、COMBINE组和IPC组心肌梗死面积明显增大；与IR组相比,LRIPOC组、SEVPOC组、COMBINE组和IPC组心肌梗死面积明显缩小；与IPC组相比,心肌梗死面积在COMBINE组无显著统计学差异,在LRIPOC组和SEVPOC组明显增大；与COMBINE组相比,LRIPOC组和SEVPOC组心肌梗死面积明显增大。
第二部分：HIF-1在联合应用远隔缺血后处理和七氟烷后处理心肌保护作用中的地位
采用8周龄、体重250-320g的健康SD大鼠建立在体心肌缺血再灌注损伤模型,即结扎大鼠LAD实施局部心肌缺血30min后开放LAD实施心肌血流再灌注60min。共分五个实验组(每组5只大鼠)：缺血再灌注损伤组(IR组)、缺血预处理组(IPC组)、肢体远隔缺血后处理组(LRIPOC组)、七氟烷后处理组(SEVPOC组)以及联合应用肢体远隔缺血后处理和七氟烷后处理组(COMBINE组)。实验过程中维持大鼠直肠温度在37-38℃范围内。再灌注末,再次结扎大鼠LAD,并迅速摘取大鼠心脏。留取结扎线以下颜色灰白的左心室组织作为缺血区心肌组织,留取右心室作为非缺血区心肌组织；同时留取大鼠后肢肌肉(触发远隔缺血后处理的组织)和前肢肌肉(非触发组织)。采用实时定量PCR技术检测(2-ΔΔct法)组织内HIF-1α、HO-1和iNOS基因的表达。
非缺血心肌组织目的基因的表达情况如下：
非缺血区心肌组织内HIF-1αmRNA表达量的均值是按照IR组、LRIPOC组、SEVPOC组.COMBINE组和IPC组的顺序递增。与IR组相比,LRIPOC组、SEVPOC组、COMBINE组和IPC组非缺血区心肌组织内HIF-1α mRNA表达量明显增高；与IPC组相比,LRIPOC组、SEVPOC组和COMBINE组非缺血区心肌组织内HIF-1α mRNA表达量明显降低；与LRIPOC组相比,非缺血区心肌组织内HIF-1α mRNA表达量在SEVOPOC组无显著统计学差异,在COMBINE组明显增高。与SEVPOC组相比,COMBINE组非缺血区心肌组织内HIF-1αmRNA的表达量明显增高。
非缺血心肌组织内HO-1mRNA表达量的均值是按照IR组、LRIPOC组、SEVPOC组、COMBINE组和IPC组的顺序递增。与IR组相比,非缺血心肌组织内HO-1mRNA表达量在LRIPOC组和SEVPOC组无显著统计学差异,在COMBINE组和IPC组明显增高；与IPC组相比,非缺血心肌组织内HO-1mRNA表达量在COMBINE组无显著统计学差异,在LRIPOC组和SEVPOC组明显降低。与LRIPOC组相比,SEVPOC组和COMBINE组非缺血心肌组织内HO-1mRNA表达量明显增高；与SEVPOC组相比,COMBINE组非缺血心肌组织内HO-1mRNA表达量明显增高。
非缺血心肌组织内iNOS mRNA表达量的均值是按照IR组、LRIPOC组、SEVPOC组、COMBINE组和IPC组的顺序递增。与IR组相比,非缺血心肌组织内iNOS mRNA表达量在LRIPOC组无显著统计学差异,在SEVPOC组、COMBINE组和IPC组明显增高；与IPC组相比,非缺血心肌组织内iNOS mRNA表达量在COMBINE组无显著统计学差异,在LRIPOC组和SEVPOC组明显降低；与LRIPOC组相比,非缺血心肌组织内iNOS mRNA表达量在SEVPOC组无显著统计学差异,在COMBINE组明显增高；与SEVPOC组相比,COMBINE组非缺血心肌组织内iNOS mRNA表达量无显著统计学差异。
缺血心肌组织目的基因的表达情况如下：
缺血区心肌组织内HIF-1α mRNA表达量的均值是按照IR组、LRIPOC组、SEVPOC组、COMBINE组和IPC组的顺序递增。与IR组相比,LRIPOC组、SEVPOC组、COMBINE组和IPC组缺血区心肌组织内HIF-1α mRNA表达量明显增高；与IPC组相比,LRIPOC组、SEVPOC组和COMBINE组缺血区心肌组织内HIF-1α mRNA表达量明显降低；LRIPOC组、SEVPOC组和COMBINE组缺血区心肌组织内HIF-1α mRNA表达量比较差异无显著统计学意义。
缺血区心肌组织内HO-1mRNA的表达量的均值是按照IR组、IPC组、SEVPOC组、COMBINE组和LRIPOC组的顺序递增。与IR组相比,LRIPOC组、SEVPOC组、COMBINE组和IPC组缺血区心肌组织内HO-1mRNA表达量明显增高；LRIPOC组、SEVPOC组、COMBINE组和IPC组缺血区心肌组织内HO-1mRNA表达量比较差异无显著统计学意义。
缺血区心肌组织内iNOS mRNA表达量的均值是按照IR组、SEVPOC组、IPC组、COMBINE组和LRIPOC组的顺序递增。与IR组相比,LRIPOC组、SEVPOC组、COMBINE组和IPC组缺血区心肌组织内iNOS mRNA表达量明显增高；与IPC组相比,缺血区心肌组织内iNOS mRNA表达量在SEVPOC组和COMBINE组无显著统计学差异,在LRIPOC组明显增高；与LRIPOC组相比,SEVPOC组和COMBINE组缺血区心肌组织内iNOS mRNA表达量明显降低。
第三部分PI3K/Akt和ERKl/2信号转导通路在联合应用远隔缺血后处理和七氟烷后处理心肌保护作用中的地位
采用8周龄、体重250-320g的健康SD大鼠建立在体心肌缺血再灌注损伤模型,即结扎大鼠LAD实施心肌缺血30min,然后开放LAD实施心肌血流再灌注60min。共分五个实验组(每组5只大鼠)：缺血再灌注损伤组(IR组)、缺血预处理组(IPC组)、肢体远隔缺血后处理组(LRIPOC组)、七氟烷后处理组(SEVPOC组)以及联合应用肢体远隔缺血后处理和七氟烷后处理组(COMBINE组)。实验过程中维持大鼠直肠温度在37-38℃。再灌注期末,再次结扎LAD,并迅速摘取心脏。留取结扎线以下颜色灰白的左心室组织作为缺血区心肌组织,留取右心室作为非缺血区心肌组织。采用Western-Blot技术检测大鼠心肌组织内Akt、磷酸化p-Akt、ERK1/2和磷酸化p-ERK1/2的表达情况,并计算p-Akt与Akt的比值以及p-ERK1/2与ERK1/2的比值。
结果显示：缺血区心肌组织内p-Akt/Akt比值的各组间比较是IR组的数值最小,并按照LRIPOC组、SEVPOC组、COMBINE组和IPC组的顺序递增。缺血区心肌组织内p-Akt/Akt比值的组间比较结果如下：与IR组相比,LRIPOC组、SEVPOC组、COMBINE组和IPC组缺血区心肌组织内p-Akt/Akt比值明显升高；与IPC组相比,LRIPOC组、SEVPOC组和COMBINE组缺血区心肌组织内p-Akt/Akt比值明显降低；与LRIPOC组相比,缺血区心肌组织内p-Akt/Akt比值在SEVPOC组无显著统计学差异,在COMBINE组明显升高；与SEVPOC组相比,COMBINE组缺血区心肌组织内p-Akt/Akt比值明显升高。
非缺血区心肌组织内p-Akt/Akt比值与缺血区心肌组织相似,同样也是IR组的数值最小,并按照LRIPOC组、SEVPOC组、COMBINE组和IPC组的顺序递增。非缺血区心肌组织内p-Akt/Akt比值的组间比较结果如下：与IR组相比,LRIPOC组、SEVPOC组、COMBINE组和IPC组非缺血区心肌组织内p-Akt/Akt比值明显升高；与IPC组相比,非缺血区心肌组织内p-Akt/Akt比值在LRIPOC组和SEVPOC组明显降低,在COMBINE组无显著统计学差异；与LRIPOC组相比,非缺血区心肌组织内p-Akt/Akt比值在SEVPOC组无显著统计学差异,在COMBINE组明显升高；与SEVPOC组相比,COMBINE组非缺血区心肌组织内p-Akt/Akt比值明显升高。
缺血区心肌组织内p-ERK/ERK比值的各组间比较是IR组的数值最小,并按照LRIPOC组、SEVPOC组、COMBINE组和IPC组的顺序递增。缺血区心肌组织内p-ERK/ERK比值的组间比较结果如下：与IR组相比,LRIPOC组、SEVPOC组、COMBINE组和IPC组缺血区心肌组织内p-ERK/ERK比值明显升高；与IPC组相比,缺血区心肌组织内p-ERK/ERK比值在LRIPOC组和SEVPOC组明显降低,在COMBINE组无显著统计学差异；与LRIPOC组相比,缺血区心肌组织内p-ERK/ERK比值在SEVPOC组无显著统计学差异,在COMBINE组明显升高；与SEVPOC组相比,COMBINE组缺血区心肌组织内p-ERK/ERK比值明显升高。
非缺血区心肌组织内p-ERK/ERK比值与缺血区心肌组织相似,同样也是IR组的数值最小,并按照LRIPOC组、SEVPOC组、COMBINE组和IPC组的顺序递增。非缺血区心肌组织内p-ERK/ERK比值的组间比较结果如下：与IR组相比,LRIPOC组、SEVPOC组、COMBINE组和IPC组非缺血区心肌组织内p-ERK/ERK比值明显升高；与IPC组相比,非缺血区心肌组织内p-ERK/ERK比值在LRIPOC组和SEVPOC组明显降低,在COMBINE组无显著统计学差异；与LRIPOC组相比,非缺血区心肌组织内p-ERK/ERK比值在SEVPOC组无显著统计学差异,在COMBINE组明显升高；与SEVPOC组相比,COMBINE组非缺血区心肌组织内p-ERK/ERK比值明显升高。
结论
通过本实验,我们得出以下结论：
1.在大鼠在体心肌缺血再灌注损伤模型,肢体远隔缺血后处理和七氟烷后处理均能有效减轻心肌缺血再灌注损伤；联合应用两种干预措施能够进一步减轻心肌缺血再灌注损伤。
2.肢体远隔缺血后处理和七氟烷后处理均能诱发系统性保护作用,即两种干预措施均能诱发缺血区心肌、非缺血区心肌、缺血区下肢肌肉内HIF-1α、HO-1和iNOS基因表达加强；联合应用两种干预措施能够进一步增强上述基因的表达。
3.肢体远隔缺血后处理和七氟烷后处理均能诱导Akt和ERK1/2磷酸化,提示这两种干预措施对心肌缺血再灌注损伤的保护作用是通过激活RISK途径实现的。
Since the phenomenon of ischemia-reperfusion injury was first reported by Jennings in the year of1960, it has been perplexing researchers for more than half a century. In order to attenuate ischemia reperfusion injury (IRI) and finally reduce infarct size of myocardium, lots of interventions have been invented. Ischemic preconditioning-the most powerful therapeutic strategy is confined to laboratory study because of the unpredictability of an acute myocardial infarction. Besides the classical stimulus of short-term ischemia, there are several stimuli that may induce a preconditioning-like effect. The cardioprotection of sevoflurane has been proven by laboratory and clinical trials and may be a tool to win our battle against the ischemia-reperfusion injury. While remote ischemic postconditioning is elicited by one or cycles of non-lethal ischemia-reperfusion to an organ or tissue remote from the heart. Its cardioprotective effect has been translated into the clinical setting with the discovery that the remote stimulus can be non-invasively induced using a standard blood pressure cuff placed on the upper arm or leg.
Hypoxia inducible factor1is an important transcriptive factor that regulates the expression of more than a hundred of genes related to hypoxia adaptation. Its downstream genes heme oxygenase1and inducible nitric oxide synthase have been proven involved in cardioprotection. Akt and ERK1/2are important components of the reperfusion injury salvage kinase (RISK) pathway, and the convergent point of many irrelevant measures. Activation of the RISK signaling pathway can exert strong protective effect against IRI.
Multi-model therapy has become a research focus in the IRI cardioprotection field in an attempt to augment the beneficial effect of strategies with different mechanism. This experiment was designed to investigate:1) cardioprotection of sevoflurane postconditioning and remote ischemic postconditioning;2) whether there is synergistic cardioprotection by combining the two strategies;3) role of HIF-1α, HO-1and iNOS in the two strategies;4) role of Akt and ERK1/2in the two strategies. This study was divided into three parts.
Part One Experimental study on cardioprotection of combining sevoflurane postconditioning and remote limb ischemic postconditioning against ischemia reperfusion injury in rat heart in vivo
Sixty healthy male Sprague Dawley rats were randomly allocated into six groups:(1) control group (CON);(2) ischemia reperfusion group (IR);(3) ischemic preconditioning group (IPC);(4) limb remote ischemic postconditioning group (LRIPOC);(5) sevoflurane postconditioning group (SEVPOC);(6) combination of limb remote ischemic postconditioning and sevoflurane postconditioning group (COMBINE). After left thoracotomy, a5-0silk ligature was passed below a main branch of the left coronary artery. The ends of the ligature were passed through a propylene tube to form a snare. Rats except the ones in the control group endured regional ischemia reperfusion injury by occlusion of the LAD for30min and then loosening for120min. In IR group, no additional intervention was performed. In IPC group, rats underwent three consercutive5-min LAD occlusion followed by5-min reperfusion before the30-min LAD ligation. In LRIPOC group, after15min of LAD ligation, blood flow in the bilateral hind limbs was stopped for10min and opened at5min before reperfusion. In SEVPOC group, rats received a10-min episode of1MAC sevoflurane5min before reperfusion and5min after reperfusion. In COMBINE group, after15min of LAD ligation, blood flow in the bilateral hind limbs was stopped for10min and opened at5min before reperfusion, and rats began a10-min episode of1MAC sevoflurane just at the time when the remote ischemia stimulus was stopped. The rectal temperature was sustained at37℃～38℃. Heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP) and lead Ⅱ electrocardiogram were continuously monitored. Arterial blood sample were taken at120min of reperfusion, and the concentration of serum LDH, CK-MB and cTnI were measured by rat ELISA kits. At the end of reperfusion, infarct size (IS%) was assessed by Evans Blue and triphenyltetrazolium chloride staining.
Forty-nine rats were finally included in this experiment (9in the CON group,8in any of the rest groups) and results showed that rat's body weight, rectal temperature and the hemodynamic parameter did not differ among the six groups (P>0.05).
Compared with IPC group, the number of rats suffering ischemic arrhythmia and arrhythmia score were significantly increased in IR group, LRIPOC group, SEVPOC group and COMBINE group. Sevoflurane could postphone ischemic arrhythmia.
Serum concentration of LDH and cTnI in the IR group, LRIPOC group, SEVPOC group, COMBINE group and IPC group were significantly higher when compared with CON group. Compared with IR group, they were significantly lower in the LRIPOC group, SEVPOC group, COMBINE group and IPC group. They were similar in the LRIPOC group and SEVPOC group, and both were significantly higher than in COMBINE group. They were similar in COMBINE group and IPC group. Serum concentration of CK-MB in the IR group, LRIPOC group and SEVPOC group was higher when compared with CON group. Compared with IR group, it was significantly lower in LRIPOC group, SEVPOC group, COMBINE group and IPC group. It was higher in LRIPOC group and SEVPOC group than in IPC group but was not statistically higher than COMBINE group.
IS%in the IR group, LRIPOC group, SEVPOC group, COMBINE group and IPC group was significantly higher when compared with CON group. Compared with IR group, it was significantly lower in LRIPOC group, SEVPOC group, COMBINE group and IPC group. It was similar in LRIPOC group and SEVPOC group, and both were significantly higher than COMBINE group. It was similar in COMBINE group and IPC group.
Part Two Experimental study on the expression of HIF-la, HO-1and iNOS in limb remote ischemic postconditioing and sevoflurane postconditioning
Twenty-five healthy male SD rats were randomly allocated into five groups:(1) ischemia reperfusion group;(2) ischemic preconditioning group;(3) limb remote ischemic postconditioning group;(4) sevoflurane postconditioning group;(5) combination of limb remote ischemic postconditioning and sevoflurane postconditioning group. After left thoracotomy, a5-0silk ligature was passed below a main branch of the left coronary artery. The ends of the ligature were passed through a propylene tube to form a snare. Rats endured regional ischemia reperfusion injury by occlusion of the LAD for30min and then loosening for60min. Hearts were excised at the termination of experiments. The part of the anterior wall of the left ventricular myocardium near the cardiac apex was separated as the ischemic myocardium, and the right atrium was separated as the non-ischemic myocardium, and skeletal muscle of the hind limb was excised as the remote ischemic tissue and skeletal muscle of the fore limb was also excised as the remote non-ischemic tissue. Real time quantitative polymerase chain reaction (RQ-PCR) was used to quantify the gene expression of hypoxia inducible factor1αand heme oxygenase1and inducible nitrix oxide synthase in these tissues.
In the non-ischemic myocardium, the expression of HIF-1αmRNA was escalated in an order of IR group, LRIPOC group, SEVPOC group, COMBINE group and IPC group. HIF-1αin IR group was significantly lower than in the other groups. The mRNA expression was significantly higher in COMBINE group than in IR group, LRIPOC group and SEVPOC group, and significantly lower than in IPC group. There was no difference between LRIPOC group and SEVPOC group. There is no difference between COMBINE group and IPC group in the expression of HO-1mRNA, and they were higher than in IR group, LRIPOC group and SEVPOC group. There is no difference between the expression of HO-1mRNA in LRIPOC group and SEVPOC group and they were higher than in IR group but without statistical differences. The expression of iNOS mRNA was significantly lower in IR group than in other groups. It was significantly higher in COMBINE group than in IR group, LRIPOC group, SEVPOC group, but significantly lower than in IPC group. There was no difference between LRIPOC group and SEVPOC group.
In the ischemic myocardium, the expression of HIF-lamRNA was significantly lower in IR group than in other groups and it was significantly higher in IPC group than in other groups. There was no difference among LRIPOC group, SEVPOC group and COMBINE group. The expression of HO-1mRNA was significantly lower in IR group than in the other groups. There was no significant difference among LRIPOC group, SEVPOC group, COMBINE group and IPC group. The expression of iNOS mRNA was significantly lower in IR group than in other groups and it was significantly higher in LRIPOC group than in other groups. There was no difference among SEVPOC group, COMBINE group and IPC group.
In the fore limb, the HIF-lamRNA expression was similar in IR group, LRIPOC group and SEVPOC group, and they were significantly lower than in IPC group and COMBINE group. There was no significant difference between IPC group and COMBINE group. The expression of HO-1mRNA was escalated in an order of IR group, SEVPOC group, LRIPOC group, IPC group and COMBINE group. However, there was no significant difference among IR group, SEVPOC group and LRIPOC group. There was no significant difference among SEVPOC group and LRIPOC and IPC group. The expression of iNOS was significantly higher in COMBINE group than in other groups. There was no difference between the other groups.
In the hind limb, the expression of HIF-1αmRNA was escalated in an order of IR group, LRIPOC group, SEVPOC group, IPC group and COMBINE group. There was no difference between LRIPOC group and SEVPOC group. There was no difference between SEVPOC group and COMBINE group. No differences existed between COMBINE group and IPC group. The expression of HO-1mRNA was escalated in in an order of IR group, SEVPOC group, LRIPOC group, IPC group and COMBINE group. There was no difference between SEVPOC group and LRIPOC group. It was significantly lower in IPC group than in COMBINE group, but significantly higher than in IR group, SEVPOC group and LRIPOC group. The expression of iNOS mRNA was escalated in an order of IR group, LRIPOC group, SEVPOC group, IPC group and COMBINE group. There was no significant difference between IR group and LRIPOC group. There was no significant difference between IPC group and COMBINE group. Part Three Experimental study on the expression of Akt and ERK in limb remote ischemic postconditioing and sevoflurane postconditioning
Twenty-five healthy male Sprague Dawley rats were randomly allocated into five groups:(1) ischemia reperfusion group;(2) ischemic preconditioning group;(3) limb remote ischemic postconditioning group;(4) sevoflurane postconditioning group;(5) combination of remote ischemic postconditioning and sevoflurane postconditioning group. After left thoracotomy, a5-0silk ligature was passed below a main branch of the left coronary artery. The ends of the ligature were passed through a propylene tube to form a snare. Rats endured regional ischemia reperfusion injury by occlusion of the LAD for30min and then loosening for60min. Hearts were removed at the termination of experiments. The part of the anterior wall of the left ventricular myocardium near the cardiac apex was separated as the ischemic myocardium, and the right atrium was separated as the non-ischemic myocardium. Western-Blot was used to examine the expression of Akt, p-Akt, ERK1/2and p-ERK1/2and caculated ratios of p-Akt/Akt and (p-ERK1/2)/(ERK1/2).
In the ischemic myocardium, the ratio of p-Akt/Akt was escalated in an order of LRIPOC group, SEVPOC group, COMBINE group and IPC group. There was no significant difference between RIPOC group and SEVPOC group. While in the non-ischemic myocardium, the p-Akt/Akt ratio was also escalated in an order of LRIPOC group, SEVPOC group, COMBINE group and IPC group. There was no difference between COMBINE group and IPC group.
In the ischemic myocardium, the ratio of (p-ERK1/2)/(ERK1/2) was escalated in an order of LRIPOC group, SEVPOC group, COMBINE group and IPC group. There was no significant difference between LRIPOC group and SEVPOC group. There was no significant difference between COMBINE group and IPC group. While in the non-ischemic myocardium, the (p-ERK1/2)/(ERK1/2) ratio was also escalated in an order of IR group, LRIPOC group, SEVPOC group, COMBINE group and IPC group. There was no significant difference between LRIPOC group and SEVPOC group. There was no significant difference between COMBINE group and IPC group.
Conclusions
Based on the results of all experiments, the following conclusion can be drawn:
1. Remote limb ischemic postconditioning and sevoflurane postconditioning provides cardioprotection against ischemia-reperfusion injury in rat hearts in vivo. Combination of the two interventions can produce an augmented protective effect.
2. Both limb remote ischemic postconditioning and sevoflurane postconditioning can trigger system response to ischemia reperfusion injury. They provoke gene expression of HIF-la, HO-1and iNOS in ischemic myocardium, non-ischemic myocardium, hind limb skeletal muscle and fore limb skeletal muscle.
3. Both limb remote ischemic postconditioning and sevoflurane postconditioning can induce the phosphorylation of Akt and ERK1/2, so the RISK signaling pathway participates in the cardioprotection of the two interventions.
低氧诱导因子1(hypoxia-inducible factor1, HIF-1)能够在转录水平调节多种基因的表达,在细胞和组织缺血适应过程中发挥着至关重要的作用。其下游基因血红素氧化酶1(Heme oxygenase1, HO-1)和诱生型一氧化氮合酶(inducible nitric oxide synthase, iNOS)具有保护心肌对抗缺血再灌注损伤的作用。丝氨酸／苏氨酸激酶Akt和细胞外调节蛋白激酶(extracellular regulated protein kinases, ERK1/2)是再灌注损伤救援激酶途径(reperfusion injury salvage kinase pathway, RISK途径)的重要组成成分,是各种不同干预措施发挥心肌保护作用的交汇点。在缺血再灌注过程中, RISK途径激活能够对心肌损伤产生强大的保护作用。
本实验从临床应用出发,拟观察联合应用两种极具应用前景的干预措施—七氟烷后处理和肢体远隔缺血后处理能否获得有益的协同性心肌保护作用。同时对缺血缺氧过程中关键转录因子HIF-1的表达情况以及RISK途径的激活情况进行观察,以初步探讨这两种干预措施发挥作用的机制。全部实验共分三个部分：
第一部分：联合应用肢体远隔缺血后处理和七氟烷后处理组处理对心肌缺血再灌注损伤的保护作用
采用8周龄、体重250-320g的健康Sprague Dawley (SD)大鼠建立在体心肌缺血再灌注损伤模型,共分六个实验组(每组10只大鼠)：空白对照组(CON组)、缺血再灌注损伤组(IR组)、缺血预处理组(IPC组)、肢体远隔缺血后处理组(LRIPOC组)、七氟烷后处理组(SEVPOC组)以及联合应用肢体远隔缺血后处理和七氟烷后处理组(COMBINE组)。所有大鼠开胸后采用5-0丝线将冠状动脉左前降支(left anterior descending coronary artery, LAD)套扎做成活结。除CON组之外,所有大鼠均接受阻断LAD局部心肌缺血30min和开放LAD心肌血流再灌注120min的处理。IR组不采取任何其他措施；IPC组结扎LAD前进行3个循环(每个循环为5min缺血-5min再灌注)的缺血预处理,总处理时间为30min；LRIPOC组在心肌缺血15min时采用止血带结扎大鼠双侧后肢造成缺血10min,并在再灌注前5min开放后肢血流灌注；SEVPOC组在开放LAD实施再灌注前5min经小动物麻醉机的挥发罐吸入1MAC的七氟烷,直至再灌注后5min；COMBINE组在心肌缺血15min时采用止血带结扎大鼠双侧后肢造成肢体缺血10min,再灌注前5min开放后肢血流灌注,并吸入1MAC的七氟烷,直至再灌注后5min。实验过程中维持大鼠直肠体温在37-38℃范围内,连续监测心率(heart rate, HR)、收缩压(systolic blood pressure, SBP)、舒张压(diastolic blood pressure, DBP)、平均动脉压(mean arterial pressure, MAP)和Ⅱ导联ECG,并计算HR和SBP的乘积(rate-pressure product, RPP)作为心肌氧耗指数。记录实验中心律失常情况并进行评分。在再灌注120min时抽取动脉血标本,采用ELISA试剂盒检测大鼠血清乳酸脱氢酶(lactic dehydrogenase, LDH)、肌酸激酶心肌型同工酶(creatine kinase MB isoenzyme, CK-MB)和心肌肌钙蛋白I(cardiac Troponin-Ⅰ, cTnⅠ),并采用伊文思蓝和氯化三苯基四氮唑(TTC)双重染色测定梗死面积(infarct size, IS%)。
排除实验中不合格的大鼠,最终共有49只大鼠纳入实验,其中CON组9只,IR组、LRIPOC组、SEVPOC组、COMBINE组个IPC组各8只。各组大鼠的一般情况、缺血面积占左心室比值各组间比较差异均无统计学意义。
与IR组相比,LRIPOC组、SEVPOC组和COMBINE组再灌注初期发生心律失常的动物数有所减少和心律失常的持续时间有不同程度的缩短,但是差异无统计学意义。与IPC组相比,IR组、LRIPOC组、SEVPOC组和COMBINE组再灌注初期发生心律失常的动物数显著增多,心律失常持续时间和心律失常评分明显升高。
血清LDH浓度的总体组间比较差异有显著统计学意义(F=51.503,P<0.01)。与CON组相比,IR组、LRIPOC组、SEVPOC组、COMBINE组和IPC组血清LDH浓度明显升高；与IR组相比,LRIPOC组、SEVPOC组、COMBINE组和IPC组血清LDH浓度明显降低；与IPC组相比,COMBINE组血清LDH浓度无显著统计学差异,但LRIPOC组和SEVPOC组血清LDH浓度明显升高；LRIPOC组和SEVPOC组血清LDH浓度比较差异无显著统计学意义；与COMBINE组相比,LRIPOC组和SEVPOC组血清LDH浓度明显升高。
血清CK-MB浓度的总体组间比较差异有显著统计学意义(F=32.244,P<0.01)。与CON组相比,血清CK-MB浓度在IPC组和COMBINE组无显著统计学差异,在IR组、LRIPOC组和SEVPOC组明显升高；与IR组相比,LRIPOC组、SEVPOC组、COMBINE组和IPC组血清CK-MB浓度明显降低；与IPC组相比,LRIPOC组和SEVPOC组血清CK-MB浓度的明显升高；与COMBINE组相比,LRIPOC组和SEVPOC组血清CK-MB浓度无显著统计学差异。
血清cTnI浓度的总体组间比较差异有显著统计学意义(F=81.511,P<0.01)。与CON组相比,IR组、LRIPOC组、SEVPOC组、COMBINE组和IPC组血清cTnl浓度明显升高；与IR组相比,LRIPOC组、SEVPOC组、COMBINE组和IPC组血清cTnI浓度明显降低；与IPC组相比,血清cTnI浓度在COMBINE组无显著统计学差异,在LRIPOC组和SEVPOC组明显升高；LRIPOC组和SEVPOC组血清cTnI浓度比较差异无显著统计学意义；与COMBINE组相比,LRIPOC组和SEVPOC组血清cTnI浓度明显升高。
各组的心肌梗死面积(IS%值)为：CON组,(3.7±3.4)%；IR组,(64.2±13.6))%：LRIPOC组,(45.8±15.6)%；SEVPOC组,(43.6±9.7)%；COMBINE组,(30.9±11.3)%；IPC组,(22.0±5.0)%。IS%值的总体组间比较差异具有显著统计学意义(F=33.333,P<0.01)。心肌梗死面积两组之间的比较结果如下：与CON组相比,IR组、LRIPOC组、SEVPOC组、COMBINE组和IPC组心肌梗死面积明显增大；与IR组相比,LRIPOC组、SEVPOC组、COMBINE组和IPC组心肌梗死面积明显缩小；与IPC组相比,心肌梗死面积在COMBINE组无显著统计学差异,在LRIPOC组和SEVPOC组明显增大；与COMBINE组相比,LRIPOC组和SEVPOC组心肌梗死面积明显增大。
第二部分：HIF-1在联合应用远隔缺血后处理和七氟烷后处理心肌保护作用中的地位
采用8周龄、体重250-320g的健康SD大鼠建立在体心肌缺血再灌注损伤模型,即结扎大鼠LAD实施局部心肌缺血30min后开放LAD实施心肌血流再灌注60min。共分五个实验组(每组5只大鼠)：缺血再灌注损伤组(IR组)、缺血预处理组(IPC组)、肢体远隔缺血后处理组(LRIPOC组)、七氟烷后处理组(SEVPOC组)以及联合应用肢体远隔缺血后处理和七氟烷后处理组(COMBINE组)。实验过程中维持大鼠直肠温度在37-38℃范围内。再灌注末,再次结扎大鼠LAD,并迅速摘取大鼠心脏。留取结扎线以下颜色灰白的左心室组织作为缺血区心肌组织,留取右心室作为非缺血区心肌组织；同时留取大鼠后肢肌肉(触发远隔缺血后处理的组织)和前肢肌肉(非触发组织)。采用实时定量PCR技术检测(2-ΔΔct法)组织内HIF-1α、HO-1和iNOS基因的表达。
非缺血心肌组织目的基因的表达情况如下：
非缺血区心肌组织内HIF-1αmRNA表达量的均值是按照IR组、LRIPOC组、SEVPOC组.COMBINE组和IPC组的顺序递增。与IR组相比,LRIPOC组、SEVPOC组、COMBINE组和IPC组非缺血区心肌组织内HIF-1α mRNA表达量明显增高；与IPC组相比,LRIPOC组、SEVPOC组和COMBINE组非缺血区心肌组织内HIF-1α mRNA表达量明显降低；与LRIPOC组相比,非缺血区心肌组织内HIF-1α mRNA表达量在SEVOPOC组无显著统计学差异,在COMBINE组明显增高。与SEVPOC组相比,COMBINE组非缺血区心肌组织内HIF-1αmRNA的表达量明显增高。
非缺血心肌组织内HO-1mRNA表达量的均值是按照IR组、LRIPOC组、SEVPOC组、COMBINE组和IPC组的顺序递增。与IR组相比,非缺血心肌组织内HO-1mRNA表达量在LRIPOC组和SEVPOC组无显著统计学差异,在COMBINE组和IPC组明显增高；与IPC组相比,非缺血心肌组织内HO-1mRNA表达量在COMBINE组无显著统计学差异,在LRIPOC组和SEVPOC组明显降低。与LRIPOC组相比,SEVPOC组和COMBINE组非缺血心肌组织内HO-1mRNA表达量明显增高；与SEVPOC组相比,COMBINE组非缺血心肌组织内HO-1mRNA表达量明显增高。
非缺血心肌组织内iNOS mRNA表达量的均值是按照IR组、LRIPOC组、SEVPOC组、COMBINE组和IPC组的顺序递增。与IR组相比,非缺血心肌组织内iNOS mRNA表达量在LRIPOC组无显著统计学差异,在SEVPOC组、COMBINE组和IPC组明显增高；与IPC组相比,非缺血心肌组织内iNOS mRNA表达量在COMBINE组无显著统计学差异,在LRIPOC组和SEVPOC组明显降低；与LRIPOC组相比,非缺血心肌组织内iNOS mRNA表达量在SEVPOC组无显著统计学差异,在COMBINE组明显增高；与SEVPOC组相比,COMBINE组非缺血心肌组织内iNOS mRNA表达量无显著统计学差异。
缺血心肌组织目的基因的表达情况如下：
缺血区心肌组织内HIF-1α mRNA表达量的均值是按照IR组、LRIPOC组、SEVPOC组、COMBINE组和IPC组的顺序递增。与IR组相比,LRIPOC组、SEVPOC组、COMBINE组和IPC组缺血区心肌组织内HIF-1α mRNA表达量明显增高；与IPC组相比,LRIPOC组、SEVPOC组和COMBINE组缺血区心肌组织内HIF-1α mRNA表达量明显降低；LRIPOC组、SEVPOC组和COMBINE组缺血区心肌组织内HIF-1α mRNA表达量比较差异无显著统计学意义。
缺血区心肌组织内HO-1mRNA的表达量的均值是按照IR组、IPC组、SEVPOC组、COMBINE组和LRIPOC组的顺序递增。与IR组相比,LRIPOC组、SEVPOC组、COMBINE组和IPC组缺血区心肌组织内HO-1mRNA表达量明显增高；LRIPOC组、SEVPOC组、COMBINE组和IPC组缺血区心肌组织内HO-1mRNA表达量比较差异无显著统计学意义。
缺血区心肌组织内iNOS mRNA表达量的均值是按照IR组、SEVPOC组、IPC组、COMBINE组和LRIPOC组的顺序递增。与IR组相比,LRIPOC组、SEVPOC组、COMBINE组和IPC组缺血区心肌组织内iNOS mRNA表达量明显增高；与IPC组相比,缺血区心肌组织内iNOS mRNA表达量在SEVPOC组和COMBINE组无显著统计学差异,在LRIPOC组明显增高；与LRIPOC组相比,SEVPOC组和COMBINE组缺血区心肌组织内iNOS mRNA表达量明显降低。
第三部分PI3K/Akt和ERKl/2信号转导通路在联合应用远隔缺血后处理和七氟烷后处理心肌保护作用中的地位
采用8周龄、体重250-320g的健康SD大鼠建立在体心肌缺血再灌注损伤模型,即结扎大鼠LAD实施心肌缺血30min,然后开放LAD实施心肌血流再灌注60min。共分五个实验组(每组5只大鼠)：缺血再灌注损伤组(IR组)、缺血预处理组(IPC组)、肢体远隔缺血后处理组(LRIPOC组)、七氟烷后处理组(SEVPOC组)以及联合应用肢体远隔缺血后处理和七氟烷后处理组(COMBINE组)。实验过程中维持大鼠直肠温度在37-38℃。再灌注期末,再次结扎LAD,并迅速摘取心脏。留取结扎线以下颜色灰白的左心室组织作为缺血区心肌组织,留取右心室作为非缺血区心肌组织。采用Western-Blot技术检测大鼠心肌组织内Akt、磷酸化p-Akt、ERK1/2和磷酸化p-ERK1/2的表达情况,并计算p-Akt与Akt的比值以及p-ERK1/2与ERK1/2的比值。
结果显示：缺血区心肌组织内p-Akt/Akt比值的各组间比较是IR组的数值最小,并按照LRIPOC组、SEVPOC组、COMBINE组和IPC组的顺序递增。缺血区心肌组织内p-Akt/Akt比值的组间比较结果如下：与IR组相比,LRIPOC组、SEVPOC组、COMBINE组和IPC组缺血区心肌组织内p-Akt/Akt比值明显升高；与IPC组相比,LRIPOC组、SEVPOC组和COMBINE组缺血区心肌组织内p-Akt/Akt比值明显降低；与LRIPOC组相比,缺血区心肌组织内p-Akt/Akt比值在SEVPOC组无显著统计学差异,在COMBINE组明显升高；与SEVPOC组相比,COMBINE组缺血区心肌组织内p-Akt/Akt比值明显升高。
非缺血区心肌组织内p-Akt/Akt比值与缺血区心肌组织相似,同样也是IR组的数值最小,并按照LRIPOC组、SEVPOC组、COMBINE组和IPC组的顺序递增。非缺血区心肌组织内p-Akt/Akt比值的组间比较结果如下：与IR组相比,LRIPOC组、SEVPOC组、COMBINE组和IPC组非缺血区心肌组织内p-Akt/Akt比值明显升高；与IPC组相比,非缺血区心肌组织内p-Akt/Akt比值在LRIPOC组和SEVPOC组明显降低,在COMBINE组无显著统计学差异；与LRIPOC组相比,非缺血区心肌组织内p-Akt/Akt比值在SEVPOC组无显著统计学差异,在COMBINE组明显升高；与SEVPOC组相比,COMBINE组非缺血区心肌组织内p-Akt/Akt比值明显升高。
缺血区心肌组织内p-ERK/ERK比值的各组间比较是IR组的数值最小,并按照LRIPOC组、SEVPOC组、COMBINE组和IPC组的顺序递增。缺血区心肌组织内p-ERK/ERK比值的组间比较结果如下：与IR组相比,LRIPOC组、SEVPOC组、COMBINE组和IPC组缺血区心肌组织内p-ERK/ERK比值明显升高；与IPC组相比,缺血区心肌组织内p-ERK/ERK比值在LRIPOC组和SEVPOC组明显降低,在COMBINE组无显著统计学差异；与LRIPOC组相比,缺血区心肌组织内p-ERK/ERK比值在SEVPOC组无显著统计学差异,在COMBINE组明显升高；与SEVPOC组相比,COMBINE组缺血区心肌组织内p-ERK/ERK比值明显升高。
非缺血区心肌组织内p-ERK/ERK比值与缺血区心肌组织相似,同样也是IR组的数值最小,并按照LRIPOC组、SEVPOC组、COMBINE组和IPC组的顺序递增。非缺血区心肌组织内p-ERK/ERK比值的组间比较结果如下：与IR组相比,LRIPOC组、SEVPOC组、COMBINE组和IPC组非缺血区心肌组织内p-ERK/ERK比值明显升高；与IPC组相比,非缺血区心肌组织内p-ERK/ERK比值在LRIPOC组和SEVPOC组明显降低,在COMBINE组无显著统计学差异；与LRIPOC组相比,非缺血区心肌组织内p-ERK/ERK比值在SEVPOC组无显著统计学差异,在COMBINE组明显升高；与SEVPOC组相比,COMBINE组非缺血区心肌组织内p-ERK/ERK比值明显升高。
结论
通过本实验,我们得出以下结论：
1.在大鼠在体心肌缺血再灌注损伤模型,肢体远隔缺血后处理和七氟烷后处理均能有效减轻心肌缺血再灌注损伤；联合应用两种干预措施能够进一步减轻心肌缺血再灌注损伤。
2.肢体远隔缺血后处理和七氟烷后处理均能诱发系统性保护作用,即两种干预措施均能诱发缺血区心肌、非缺血区心肌、缺血区下肢肌肉内HIF-1α、HO-1和iNOS基因表达加强；联合应用两种干预措施能够进一步增强上述基因的表达。
3.肢体远隔缺血后处理和七氟烷后处理均能诱导Akt和ERK1/2磷酸化,提示这两种干预措施对心肌缺血再灌注损伤的保护作用是通过激活RISK途径实现的。
Since the phenomenon of ischemia-reperfusion injury was first reported by Jennings in the year of1960, it has been perplexing researchers for more than half a century. In order to attenuate ischemia reperfusion injury (IRI) and finally reduce infarct size of myocardium, lots of interventions have been invented. Ischemic preconditioning-the most powerful therapeutic strategy is confined to laboratory study because of the unpredictability of an acute myocardial infarction. Besides the classical stimulus of short-term ischemia, there are several stimuli that may induce a preconditioning-like effect. The cardioprotection of sevoflurane has been proven by laboratory and clinical trials and may be a tool to win our battle against the ischemia-reperfusion injury. While remote ischemic postconditioning is elicited by one or cycles of non-lethal ischemia-reperfusion to an organ or tissue remote from the heart. Its cardioprotective effect has been translated into the clinical setting with the discovery that the remote stimulus can be non-invasively induced using a standard blood pressure cuff placed on the upper arm or leg.
Hypoxia inducible factor1is an important transcriptive factor that regulates the expression of more than a hundred of genes related to hypoxia adaptation. Its downstream genes heme oxygenase1and inducible nitric oxide synthase have been proven involved in cardioprotection. Akt and ERK1/2are important components of the reperfusion injury salvage kinase (RISK) pathway, and the convergent point of many irrelevant measures. Activation of the RISK signaling pathway can exert strong protective effect against IRI.
Multi-model therapy has become a research focus in the IRI cardioprotection field in an attempt to augment the beneficial effect of strategies with different mechanism. This experiment was designed to investigate:1) cardioprotection of sevoflurane postconditioning and remote ischemic postconditioning;2) whether there is synergistic cardioprotection by combining the two strategies;3) role of HIF-1α, HO-1and iNOS in the two strategies;4) role of Akt and ERK1/2in the two strategies. This study was divided into three parts.
Part One Experimental study on cardioprotection of combining sevoflurane postconditioning and remote limb ischemic postconditioning against ischemia reperfusion injury in rat heart in vivo
Sixty healthy male Sprague Dawley rats were randomly allocated into six groups:(1) control group (CON);(2) ischemia reperfusion group (IR);(3) ischemic preconditioning group (IPC);(4) limb remote ischemic postconditioning group (LRIPOC);(5) sevoflurane postconditioning group (SEVPOC);(6) combination of limb remote ischemic postconditioning and sevoflurane postconditioning group (COMBINE). After left thoracotomy, a5-0silk ligature was passed below a main branch of the left coronary artery. The ends of the ligature were passed through a propylene tube to form a snare. Rats except the ones in the control group endured regional ischemia reperfusion injury by occlusion of the LAD for30min and then loosening for120min. In IR group, no additional intervention was performed. In IPC group, rats underwent three consercutive5-min LAD occlusion followed by5-min reperfusion before the30-min LAD ligation. In LRIPOC group, after15min of LAD ligation, blood flow in the bilateral hind limbs was stopped for10min and opened at5min before reperfusion. In SEVPOC group, rats received a10-min episode of1MAC sevoflurane5min before reperfusion and5min after reperfusion. In COMBINE group, after15min of LAD ligation, blood flow in the bilateral hind limbs was stopped for10min and opened at5min before reperfusion, and rats began a10-min episode of1MAC sevoflurane just at the time when the remote ischemia stimulus was stopped. The rectal temperature was sustained at37℃～38℃. Heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP) and lead Ⅱ electrocardiogram were continuously monitored. Arterial blood sample were taken at120min of reperfusion, and the concentration of serum LDH, CK-MB and cTnI were measured by rat ELISA kits. At the end of reperfusion, infarct size (IS%) was assessed by Evans Blue and triphenyltetrazolium chloride staining.
Forty-nine rats were finally included in this experiment (9in the CON group,8in any of the rest groups) and results showed that rat's body weight, rectal temperature and the hemodynamic parameter did not differ among the six groups (P>0.05).
Compared with IPC group, the number of rats suffering ischemic arrhythmia and arrhythmia score were significantly increased in IR group, LRIPOC group, SEVPOC group and COMBINE group. Sevoflurane could postphone ischemic arrhythmia.
Serum concentration of LDH and cTnI in the IR group, LRIPOC group, SEVPOC group, COMBINE group and IPC group were significantly higher when compared with CON group. Compared with IR group, they were significantly lower in the LRIPOC group, SEVPOC group, COMBINE group and IPC group. They were similar in the LRIPOC group and SEVPOC group, and both were significantly higher than in COMBINE group. They were similar in COMBINE group and IPC group. Serum concentration of CK-MB in the IR group, LRIPOC group and SEVPOC group was higher when compared with CON group. Compared with IR group, it was significantly lower in LRIPOC group, SEVPOC group, COMBINE group and IPC group. It was higher in LRIPOC group and SEVPOC group than in IPC group but was not statistically higher than COMBINE group.
IS%in the IR group, LRIPOC group, SEVPOC group, COMBINE group and IPC group was significantly higher when compared with CON group. Compared with IR group, it was significantly lower in LRIPOC group, SEVPOC group, COMBINE group and IPC group. It was similar in LRIPOC group and SEVPOC group, and both were significantly higher than COMBINE group. It was similar in COMBINE group and IPC group.
Part Two Experimental study on the expression of HIF-la, HO-1and iNOS in limb remote ischemic postconditioing and sevoflurane postconditioning
Twenty-five healthy male SD rats were randomly allocated into five groups:(1) ischemia reperfusion group;(2) ischemic preconditioning group;(3) limb remote ischemic postconditioning group;(4) sevoflurane postconditioning group;(5) combination of limb remote ischemic postconditioning and sevoflurane postconditioning group. After left thoracotomy, a5-0silk ligature was passed below a main branch of the left coronary artery. The ends of the ligature were passed through a propylene tube to form a snare. Rats endured regional ischemia reperfusion injury by occlusion of the LAD for30min and then loosening for60min. Hearts were excised at the termination of experiments. The part of the anterior wall of the left ventricular myocardium near the cardiac apex was separated as the ischemic myocardium, and the right atrium was separated as the non-ischemic myocardium, and skeletal muscle of the hind limb was excised as the remote ischemic tissue and skeletal muscle of the fore limb was also excised as the remote non-ischemic tissue. Real time quantitative polymerase chain reaction (RQ-PCR) was used to quantify the gene expression of hypoxia inducible factor1αand heme oxygenase1and inducible nitrix oxide synthase in these tissues.
In the non-ischemic myocardium, the expression of HIF-1αmRNA was escalated in an order of IR group, LRIPOC group, SEVPOC group, COMBINE group and IPC group. HIF-1αin IR group was significantly lower than in the other groups. The mRNA expression was significantly higher in COMBINE group than in IR group, LRIPOC group and SEVPOC group, and significantly lower than in IPC group. There was no difference between LRIPOC group and SEVPOC group. There is no difference between COMBINE group and IPC group in the expression of HO-1mRNA, and they were higher than in IR group, LRIPOC group and SEVPOC group. There is no difference between the expression of HO-1mRNA in LRIPOC group and SEVPOC group and they were higher than in IR group but without statistical differences. The expression of iNOS mRNA was significantly lower in IR group than in other groups. It was significantly higher in COMBINE group than in IR group, LRIPOC group, SEVPOC group, but significantly lower than in IPC group. There was no difference between LRIPOC group and SEVPOC group.
In the ischemic myocardium, the expression of HIF-lamRNA was significantly lower in IR group than in other groups and it was significantly higher in IPC group than in other groups. There was no difference among LRIPOC group, SEVPOC group and COMBINE group. The expression of HO-1mRNA was significantly lower in IR group than in the other groups. There was no significant difference among LRIPOC group, SEVPOC group, COMBINE group and IPC group. The expression of iNOS mRNA was significantly lower in IR group than in other groups and it was significantly higher in LRIPOC group than in other groups. There was no difference among SEVPOC group, COMBINE group and IPC group.
In the fore limb, the HIF-lamRNA expression was similar in IR group, LRIPOC group and SEVPOC group, and they were significantly lower than in IPC group and COMBINE group. There was no significant difference between IPC group and COMBINE group. The expression of HO-1mRNA was escalated in an order of IR group, SEVPOC group, LRIPOC group, IPC group and COMBINE group. However, there was no significant difference among IR group, SEVPOC group and LRIPOC group. There was no significant difference among SEVPOC group and LRIPOC and IPC group. The expression of iNOS was significantly higher in COMBINE group than in other groups. There was no difference between the other groups.
In the hind limb, the expression of HIF-1αmRNA was escalated in an order of IR group, LRIPOC group, SEVPOC group, IPC group and COMBINE group. There was no difference between LRIPOC group and SEVPOC group. There was no difference between SEVPOC group and COMBINE group. No differences existed between COMBINE group and IPC group. The expression of HO-1mRNA was escalated in in an order of IR group, SEVPOC group, LRIPOC group, IPC group and COMBINE group. There was no difference between SEVPOC group and LRIPOC group. It was significantly lower in IPC group than in COMBINE group, but significantly higher than in IR group, SEVPOC group and LRIPOC group. The expression of iNOS mRNA was escalated in an order of IR group, LRIPOC group, SEVPOC group, IPC group and COMBINE group. There was no significant difference between IR group and LRIPOC group. There was no significant difference between IPC group and COMBINE group. Part Three Experimental study on the expression of Akt and ERK in limb remote ischemic postconditioing and sevoflurane postconditioning
Twenty-five healthy male Sprague Dawley rats were randomly allocated into five groups:(1) ischemia reperfusion group;(2) ischemic preconditioning group;(3) limb remote ischemic postconditioning group;(4) sevoflurane postconditioning group;(5) combination of remote ischemic postconditioning and sevoflurane postconditioning group. After left thoracotomy, a5-0silk ligature was passed below a main branch of the left coronary artery. The ends of the ligature were passed through a propylene tube to form a snare. Rats endured regional ischemia reperfusion injury by occlusion of the LAD for30min and then loosening for60min. Hearts were removed at the termination of experiments. The part of the anterior wall of the left ventricular myocardium near the cardiac apex was separated as the ischemic myocardium, and the right atrium was separated as the non-ischemic myocardium. Western-Blot was used to examine the expression of Akt, p-Akt, ERK1/2and p-ERK1/2and caculated ratios of p-Akt/Akt and (p-ERK1/2)/(ERK1/2).
In the ischemic myocardium, the ratio of p-Akt/Akt was escalated in an order of LRIPOC group, SEVPOC group, COMBINE group and IPC group. There was no significant difference between RIPOC group and SEVPOC group. While in the non-ischemic myocardium, the p-Akt/Akt ratio was also escalated in an order of LRIPOC group, SEVPOC group, COMBINE group and IPC group. There was no difference between COMBINE group and IPC group.
In the ischemic myocardium, the ratio of (p-ERK1/2)/(ERK1/2) was escalated in an order of LRIPOC group, SEVPOC group, COMBINE group and IPC group. There was no significant difference between LRIPOC group and SEVPOC group. There was no significant difference between COMBINE group and IPC group. While in the non-ischemic myocardium, the (p-ERK1/2)/(ERK1/2) ratio was also escalated in an order of IR group, LRIPOC group, SEVPOC group, COMBINE group and IPC group. There was no significant difference between LRIPOC group and SEVPOC group. There was no significant difference between COMBINE group and IPC group.
Conclusions
Based on the results of all experiments, the following conclusion can be drawn:
1. Remote limb ischemic postconditioning and sevoflurane postconditioning provides cardioprotection against ischemia-reperfusion injury in rat hearts in vivo. Combination of the two interventions can produce an augmented protective effect.
2. Both limb remote ischemic postconditioning and sevoflurane postconditioning can trigger system response to ischemia reperfusion injury. They provoke gene expression of HIF-la, HO-1and iNOS in ischemic myocardium, non-ischemic myocardium, hind limb skeletal muscle and fore limb skeletal muscle.
3. Both limb remote ischemic postconditioning and sevoflurane postconditioning can induce the phosphorylation of Akt and ERK1/2, so the RISK signaling pathway participates in the cardioprotection of the two interventions.
引文
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