摘要
人体运动时常因运动强度过大导致心肌相对缺血,有时引起心肌功能障碍,严重时导致心肌结构损伤。及时恢复缺血心肌组织的血供,不仅能纠正缺血引起的心肌功能障碍,而且可以使可逆性结构变化的心肌恢复正常。但实验研究和临床研究已经发现,在短时间心肌缺血后一定时间内恢复血流,有时会使原缺血心肌的损伤加重,即出现缺血再灌注损伤。减轻缺血再灌注损伤的有效方法之一是缺血预处理,即心肌在遭受一次或多次反复短暂缺血再灌后,表现出对随后而来的长时间的严重缺血再灌注损伤的抵抗能力提高。近来研究显示,运动训练能产生类似缺血预处理效应,即运动预处理。虽然人们对运动预处理进行了一些研究,但运动预处理确切机制尚不十分清楚。因此本课题采用结扎大鼠的冠状动脉制造了在体大鼠心肌缺血再灌注损伤模型,来观察高强度间歇运动训练和一次高强度间歇运动对缺血再灌注心肌的保护作用,并对间歇运动抗心肌缺血再灌注损伤的细胞分子机制进行了研究,为寻找安全有效的防治心肌缺血再灌注损伤的非创伤性手段提供实验依据。本研究共包括五个部分。
1.间歇运动对I/R损伤大鼠心肌组织和心脏机能的影响。
采用在体结扎冠状动脉法建立大鼠的心肌I/R模型,观察高强度间歇运动训练和一次高强度间歇运动对心肌组织损伤、心电图以及心肌血清酶指标的影响,确定高强度间歇运动对缺血再灌注心脏的保护作用。
42只大鼠被随机分为4组,每组从成功造模大鼠中随机抽取8只纳入实验。(1)对照假手术组(CONT+SHAM组):以安静对照组造模,只开胸、穿线但不结扎。(2)对照模型组(CONT+I/R组):以安静对照组造模,结扎左前降支冠状动脉(LAD)30min,再灌注40min。(3)间歇运动训练模型组(IT+I/R组):以间歇运动训练大鼠造模,方法同对照模型组。(4)一次间歇运动模型组(OIE+I/R组):以一次间歇运动大鼠造模,方法同对照模型组。
分别观察各组心肌组织HE染色切片,动态心电图,心功能指标和血清心肌酶(CK、HDL和AST)。
结果显示运动训练组大鼠的心室重与体重比值显著高于安静对照组;间歇运动训练模型组和一次间歇运动模型组心肌病理性变化程度都较模型组减轻。间歇运动模型组可见心肌细胞水肿及PMN浸润,炎性细胞浸润较模型组轻,心肌受损的程度也进一步下降。一次间歇运动模型组可见点状的心肌细胞坏死,并见心肌细胞水肿变性和PMN浸润;间歇运动训练缺血再灌注损伤模型组与对照模型组相比,ST(J点)抬高程度在缺血30分钟时和再灌注40分钟时显著低于对照模型组;一次训练缺血再灌注损伤模型组大鼠的ST(J点)抬高程度在再灌注40分钟时显著低于在对照缺血再灌注损伤组。间歇运动训练缺血模型组的CK、LDH和GOT活性显著低于对照模型组;一次间歇运动模型组大鼠血清中CK和LDH活性显著低于对照组模型组,而GOT没有显著变化。缺血30分钟时,对照模型组大鼠的心功能显著低于对照假手术组,间歇运动训练组和一次间歇运动组的心功能显著高于对照缺血再灌模型组。再灌注40分钟时,对照模型组大鼠的心功能显著低于对照假手术组,间歇运动训练缺血再灌注组和一次间歇运动模型组的心功能明显高于对照缺血再灌注模型组,但一次间歇运动模型组和对照缺血再灌注模型组的LVEDP和+dp/dt_(max)无明显差异。
结果表明,高强度间歇运动训练和一次高强度间歇运动对缺血再灌注心肌产生了延迟保护作用,可以降低缺血再灌注心肌的损伤程度,减轻缺血再灌注引起的功能损失。其中高强度的间歇运动训练对心脏的保护作用更为明显。
2.间歇运动对I/R损伤大鼠心肌抗氧化防御系统的影响。
本实验目的在于通过检测丙二醛(MDA)、超氧化物歧化酶(SOD)和谷胱苷肽过氧化酶(GSH-PX)来探索自由基防御体系在间歇运动预处理抗心肌缺血再灌注损伤中的作用和初步机制。
采用上述模型和分组方法。在缺血30分钟、再灌注40分钟后取适量大鼠心肌组织,用比色法检测心肌组织中MDA、SOD和GSH-PX。
结果显示,间歇运动训练模型组和一次间歇运动模型组SOD、GSH-PX活性均高于对照模型组;间歇运动训练和一次间歇运动缺血再灌注模型组心肌组织中MDA含量明显低于对照缺血再灌注模型组。
结果表明,间歇运动增强了I/R心肌的抗氧化能力。结合间歇运动对I/R心脏机能的保护作用,推测增强其抗氧化能力,减少自由基的生成进而减少心肌细胞的自由基损伤,介导了运动预处理对I/R心脏的保护作用。
3.间歇运动对I/R损伤大鼠心肌内源性保护因子的影响。
本实验以NO和HSP70为代表,初步探索内源性保护物质在运动预处理的心脏保护作用中的介导作用和机制。
采用上述模型和分组方法。在缺血30分钟、再灌注40分钟后取适量大鼠心肌组织,用比色法测定心肌组织中一氧化氮含量和一氧化氮合酶活性,用免疫组织化学方法和免疫蛋白印迹技术检测心肌中热休克蛋白70的表达。
结果显示,间歇运动训练缺血再灌注模型组心肌组织中NO的含量显著高于对照模型组;和假手术组比对照缺血再灌注模型组心肌中cNOS显著降低,间歇运动训练模型组的cNOS明显高于对照模型组;而对照模型组iNOS明显高于假手术组,间歇运动训练模型组和一次间歇运动模型组的iNOS显著低于对照模型组,其中一次运动模型组要高于间歇运动训练模型组。间歇运动训练模型组和一次间歇运动训练模型组心肌中HSP70的表达明显增加高于对照缺血组。
结果表明,间歇运动训练通过增强cNOS的表达,抑制I/R心肌iNOS的表达,增加I/R时NO生成来提高心肌抗缺血再灌注损伤的能力。一次间歇运动主要通过抑制iNOS的活性来减少I/R时NO的毒性作用,从而保护缺血再灌注心肌。作为分子伴侣的HSP70也参与了间歇运动预处理的心脏保护作用。
4.间歇运动对I/R损伤大鼠心肌细胞凋亡及其调节基因的影响。
本实验通过检测心肌细胞凋亡和凋亡相关的基因,旨在探讨间歇运动预处理对细胞凋亡调控的关系。
采用上述模型和分组方法。在缺血30分钟、再灌注40分钟后取适量大鼠心肌组织,DNA凝胶电泳技术和原位末端标记技术检测心肌细胞的凋亡程度,用逆转录-多聚酶链式反应检测凋亡调控基因(Bcl-2和bax)的表达。
结果显示,对照缺血再灌注大鼠心肌组织基因组DNA片段分布弥散,呈现凋亡改变即DNALadder,提示细胞核内NDA被核酸内切酶降解。间歇运动训练和一次间歇运动训练组NDA弥散程度较轻,未见明显DNA Ladder。间歇运动训练和一次间歇运动可降低TUNEL染色的阳性细胞比例,细胞凋亡率低于缺血再灌注损伤组。通过RT-PCR技术检测各组大鼠心肌组织中bax和bcl-2mRNA的表达发现,间歇运动训练明显促进bcl-2的基因表达,而bax的表达显著低于对照模型组,bcl-2/bax比值显著高于对照模型组,一次间歇运动组bcl-2表达高于对照模型组,Bax表达低于对照模型组,bcl-2/bax比值显著高于对照缺血组。
实验结果表明间歇运动训练和一次间歇运动通过改变凋亡调控基因的表达而有效抑制了I/R心肌的细胞凋亡,从而表现出预处理效应。
5.间歇运动对I/R损伤大鼠心肌细胞蛋白激酶C的影响。
本实验主要从信号转导的角度,探讨PKC在间歇运动训练对I/R心肌保护作用中的地位和初步机制。
采用上述模型和分组方法。在缺血30分钟、再灌注40分钟后取适量大鼠心肌组织,用免疫组织化学方法观察PKC蛋白的表达,用逆转录-多聚酶链式反应检测PKCmRNA的表达。
结果显示,间歇运动训练模型组心肌PKC较对照模型组表达增强,一次间歇运动模型组心肌PKC较对照模型组表达增强。间歇运动训练模型组PKC表达明显高于对照缺血再灌注模型组,一次间歇运动模型组PKC表达也明显高于对照缺血再灌注模型组。
结果表明,间歇运动训练和一次间歇运动均可激活PKC。间歇运动训练和一次间歇运动对I/R心脏的保护作用可能是通过PKC途径介导的。
When people have severity sports, cardiac function often be impaired because ofrelative ischemia, myocardium sometimes be injured. Blood stream resuming afterischemia will put cardiac function and reversibility structure damage right. Butexperiments studies discovered that blood stream resuming after brief ischemiacaused myocardium injured worse because of ischemia-reperfusion injury ofmyocardium. Ischemia precondition a available way to lighten myocardium injuryinduced by ischemia-reperfusion. IPC is a phenomenon by which a brief episode(s) ofmyocardial ischemia increases the ability of the heart to a subsequent prolongedperiod of ischemic injury. There are some researches relate to exercise precondition(EP), but its mechanism keep unknown. In this study, we want to investigate thecardioprotective effect, relational cellular and molecular mechanisms of chronicinterval training and acute interval exercise preventing ischemia-reperfusion injury ofmyocardium by Sprague-Dawley rats models was established by occlusion the coronaryartery in vivo. The study aim at offer experiment evidence for search a safe andeffective means without ravage.
1. The effect of interval exercise on ischemia-reperfusion rats' myocardium andcardiac function.
The model of ischemia-reperfusion injury of rat myocardium in vivo were inducedby ligateing left coronary artery. By observe the effect of high-intensity intervaltraining and once high-intensity interval exercise on myocardium, ECG and serumenzyme from myocardium; confirm the cardioprotection of high interval exercise.
42 rats were randomly divided into four groups. 8 rats from every group thatsucceed being made model were bring into experiment. The rats in CONT+I/R GROUP from sedentary group were subjected to 30min of left anterior descendingcoronary artery (LAD) occlusion followed by 40min reperfusion. The rats inCONT+SHAM GROUP from sedentary group were operated as CONT+I/R GROUPbut didn't ligate LAD. The rats in IT+I/R GROUP were from interval training groupand the rats in OIE+I/R GROUP were from once interval exercise group, theoperation as CONT+I/R GROUP.
The purposes of the study is having histopsthologic examination of myocardium inrats and observe developmental ECG, index of cardiac function and myocardiumenzyme in serum.
The data showed that interval training make hearts of rat hypertrophy. The extent ofpathologic change in IT+I/R GROUP and OIE+I/R GROUP is less than that inCONT+I/R GROUP. At the time of ischemia 30min and reperfusion 40min, rise ofST(J point) and activities of CK, LDH and GOT in IT+I/P, GROUP is notable lessthan CONT+I/R GROUR But cardiac function in IT+I/R GROUP is significant higherthan CONT+I/R GROUP. Above index in OIT+I/R GROUP almost like IT+I/RGROUP, only GOT, LVDP and +dp/dt_(max) without significant changes compare withCONT+I/R GROUP.
The result indicated interval training and once interval exercise play an importantrole in the late phase of IPC. And the effect of high-intensity interval training isstronger than once high-intensity interval exercise.
2. The effect of interval exercise on ischemia-reperfusion rats' myocardiumantioxidant defenses capability
The experiment aim at exploring use and mechanism of free radical defensessystem in interval exercise mediated cardioprotection against ischemia-reperfusioninjure.
The model and grouping was used as previously described. Suitable myocardiumwas taken to examine MDA, SOD and GSH-Px by colorimetry after 30min ischemiaand 40min reperfusion.
The data showed that activities of SOD and GSH-Px are notable higher in IT+I/R GROUP and OIT+I/R GROUP than CONT+I/R GROUP, but content of MDA issignificant less than CONT+I/R GROUP.
The result indicated interval exercise increase antioxidant defenses capability in I/Rmyocardium, considering cardioprotection from interval exercise we presuming byreduction free radical damage and increase antioxidant defenses capability maybemediate cardioprotection of EP against I/R injury.
3. The effect of interval exercise on ischemia-reperfusion rats' myocardiumendogenous protective factors
The experiment study NO and HSP70, aim at exploring use and mechanism ofendogenous protective factors in interval exercise mediated cardioprotection againstischemia-reperfusion injure.
The model and grouping was used as previously described. Suitable myocardiumwas taken to examine NO and NOS by colorimetry, Expression Levels of HSP70 byimmunohistochemical and Western Blot means after 30min ischemia and 40minreperfusion.
The data showed that content of NO and activity of cNOS is higher in IT+I/RGROUP than CONT+I/R GROUP, but activity iNOS is less than CONT+I/R GROUP.Content of NO and activity of iNOS is higher in OIT+I/R GROUP than CONT+I/RGROUP, but activity cNOS is less than CONT+I/R GROUP. Expression Levels ofHSP70 in IT+I/R GROUP and OIT+I/R GROUP is significant higher than CONT+I/RGROUP.
The result indicated interval training enhance myocardium ability against I/R injuryby increasing expression of cNOS but restraining expression of iNOS, increasing NOcontent. Once interval exercise mainly restrain expression of iNOS and reducetoxicity of NO. As molecular chaperone HSP70 participate in cardioprotection.
4. The effect of interval exercise on ischemia-reperfusion rats' cardiac myocyteapoptosis and correlative regulation gene
The experiment examine cardiac myocyte apoptosis and correlative regulation gene,aim at exploring effect of interval exercise precondition on cardiac myocyteapoptosis.
The model and grouping was used as previously described. Suitable myocardiumwas taken to examine DNA Ladder by gel electrophoresis, apoptosis degree byTUNEL, expression of Bcl-2/bax by RT-PCR.
The data showed that apoptosis degree in IT+I/R GROUP and OIT+I/R GROUP issignificant less than CONT+I/R GROUP. Interval training promote gene expression ofBcl-2 and restrain gene expression of bax. Once interval exercise only promoteexpression of Bcl-2.
The result indicated interval training and once interval exercise efficiently restraincardiac myocyte apoptosis in I/R heart by altering expression of regulation gene.Thereby precondition come forth.
5. The effect of interval exercise on ischemia-reperfusion rats' cardiac myocyteapoptosis and correlative regulation gene
The experiment at the point of signaling transduction, aim at exploring station andmechanism of protein kinase C in interval exercise mediated cardioprotection againstischemia-reperfusion injure.
The model and grouping was used as previously described. Suitable myocardiumwas taken to examine PKC protein by immunohistochemical means, examinePKCmRNA expression by RT-PCR technique.
The data showed that expression of PKC in IT+I/R GROUP and OIT+I/R GROUPis significant higher than CONT+I/R GROUP.
The result indicated interval training and once interval exercise efficiently activatePKC and its' expression. Cardioprotection induced by interval training and onceinterval exercise maybe mediated by PKC signal pathway.
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