曲美他嗪对犬急性心肌梗死后延迟再灌注中缺血区心肌细胞凋亡的影响
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摘要
目的再灌注治疗是目前治疗急性心肌梗死(acute myocardial infarction AMI)的有效方法之一。业已证实,心肌梗死后早期恢复血液供应,能减少梗死面积,同时也可能使心肌细胞损伤进一步加重即缺血-再灌注损伤(ischemia-Reperfusion injuryIRI)。心肌梗死后的延迟再灌注(late reperusion,LR)仍然有利于改善心肌重构,保护心功能。但最近有研究显示,延迟再灌注也存在缺血-再灌注损伤现象。曲美他嗪(trimetazidine,TMZ)是一种治疗缺血性心脏病、具有抗氧化效应的代谢类药物,已广泛应用于临床;有资料报道曲美他嗪对心肌细胞早期缺血-再灌注损伤有显著的保护作用,然而在延迟再灌注中是否仍具有心肌保护作用,国内外尚未见报道。本实验通过建立犬急性心肌梗死-延迟再灌注模型,以探讨曲美他嗪在急性心肌梗死后延迟再灌注中对梗死周边缺血区心肌细胞的保护作用及其机制。
方法24只健康成年犬随机平均分为3组:假手术组、单纯延迟再灌注组(Latereperfusion group,LR)、延迟再灌注预加曲美他嗪组(Late reperfusion+rimetazidinegroup,LR+TMZ)。假手术组和LR组灌服生理盐水,LR+TMZ组灌服曲美他嗪(2mg·kg~(-1)·d~(-1))共14d。所有犬于d14灌药2h后行静脉麻醉,术中维持麻醉、心电监护、气管插管接呼吸机辅助呼吸,常规消毒,开胸。假手术组不结扎冠状动脉;LR和LR+TMZ在高位结扎左冠状动脉前降支10h,再灌注10h,制成急性心肌梗死-延迟再灌注模型。各组经上述处理后取梗死周边缺血区心肌组织。采用末端脱氧核糖核甘酸转移酶(TdT)介导的带荧光的dUTP缺口末端标记(TdT-mediated dUTP nickend labeing,TUNEL)法法测心肌细胞凋亡指数(AI),免疫组织化学法测Bcl-2、Bax、细胞色素C(Cytochrome C,cyt-c)和凋亡诱导因子(Apoptosis-inducing factor,AIF)蛋白表达。
结果与LR组相比,LR+TMZ组心肌细胞AI显著降低(p＜0.01),Bax、Cytochrome C和AIF蛋白的表达明显减少(p＜0.01),而Bcl-2蛋白的表达明显增高(p＜0.01);各指标分别与假手术组比较,差异均有显著性(p＜0.001)。
结论曲美他嗪在急性心肌梗死后延迟再灌注中可减少梗死周边缺血区心肌细胞的凋亡,其机制可能与增加Bcl-2蛋白的表达,减少Bax、细胞色素C、AIF蛋白的表达有关。
OBJECTIVE Reperfusion of acute myocardial infarction(AMI) is the most effective method at present.It has already confirmed that earlier reperfusion of ischemia myocardium can decrease the infarct size,on the other hand the cardiocyte injury may be aggravated,such phenomenon is called ischemia reperfusion injury(IRI).It has confirmed that late reperfusion of ischemia myocardium also can delay myocardium remodeling and preserve heart function.But some recent research has proved the existence of late ischemia reperfusion injury in border region of infarcted myocardium. Trimetazidine,an antioxidant agent,has been extensively used in coronary artery disease and other cardiovascular disease.Also,it has been shown that trimetazidine can inhibit myocytes from ischemia reperfusion mediated apoptosis.But it is note clear wheather trimetazidine also inhibit myocytes apoptosis from late reperfusion.We investigated the cardiopro-tection effection and the possible mechanism of trimetazidine in the risk areas during late reperfusion after acute myocardial infarct in canine.
Methods Twenty-four adult dogs were randomly divided into three groups:sham operation group(n=8),late reperfusion group(LR,n=8),and late reperfusion after trimetazidine treatment group(LR+TMZ,n=8).Physiological saline was orally given in the sham operation group and LR group and trimetazidine(2mg·kg~(-1)·d~(-1)) in the LR+TMZ group for fourteen days.Fourteen days later,all dogs were received chest operation and coronary artery was exposed.The late reperfusion of acute myocardial infarction model was made by ligating the coronary for 10 h,followed by reperfusion of 10h.Apoptotic index were detected by TUNEL.The Bcl-2,Bax,Cytochrome C and Apoptosis-inducing factor(AIF) proteins were detected by immunohistochemistry.
Results Compared with LR group,myocardial apoptotic index and the expression of Bax,Cytochrome C and AIF proteins in LR+TMZ were decreased significantly(all P＜0.01),but the expression of Bcl-2 proteins were increased(P＜0.01).Comparing with shame operation group respectively,all indicators were significantly different(p＜0.001).
Conclusion Trimetazidine can decrease cardiomyocyte apoptosis in the risk area during late reperfusion after acute myocardial infarction,which may be related to the increased expression level of Bcl-2 proteins and decreased expression level of Bax, Cytochrome C and AIF proteins.
方法24只健康成年犬随机平均分为3组:假手术组、单纯延迟再灌注组(Latereperfusion group,LR)、延迟再灌注预加曲美他嗪组(Late reperfusion+rimetazidinegroup,LR+TMZ)。假手术组和LR组灌服生理盐水,LR+TMZ组灌服曲美他嗪(2mg·kg~(-1)·d~(-1))共14d。所有犬于d14灌药2h后行静脉麻醉,术中维持麻醉、心电监护、气管插管接呼吸机辅助呼吸,常规消毒,开胸。假手术组不结扎冠状动脉;LR和LR+TMZ在高位结扎左冠状动脉前降支10h,再灌注10h,制成急性心肌梗死-延迟再灌注模型。各组经上述处理后取梗死周边缺血区心肌组织。采用末端脱氧核糖核甘酸转移酶(TdT)介导的带荧光的dUTP缺口末端标记(TdT-mediated dUTP nickend labeing,TUNEL)法法测心肌细胞凋亡指数(AI),免疫组织化学法测Bcl-2、Bax、细胞色素C(Cytochrome C,cyt-c)和凋亡诱导因子(Apoptosis-inducing factor,AIF)蛋白表达。
结果与LR组相比,LR+TMZ组心肌细胞AI显著降低(p＜0.01),Bax、Cytochrome C和AIF蛋白的表达明显减少(p＜0.01),而Bcl-2蛋白的表达明显增高(p＜0.01);各指标分别与假手术组比较,差异均有显著性(p＜0.001)。
结论曲美他嗪在急性心肌梗死后延迟再灌注中可减少梗死周边缺血区心肌细胞的凋亡,其机制可能与增加Bcl-2蛋白的表达,减少Bax、细胞色素C、AIF蛋白的表达有关。
OBJECTIVE Reperfusion of acute myocardial infarction(AMI) is the most effective method at present.It has already confirmed that earlier reperfusion of ischemia myocardium can decrease the infarct size,on the other hand the cardiocyte injury may be aggravated,such phenomenon is called ischemia reperfusion injury(IRI).It has confirmed that late reperfusion of ischemia myocardium also can delay myocardium remodeling and preserve heart function.But some recent research has proved the existence of late ischemia reperfusion injury in border region of infarcted myocardium. Trimetazidine,an antioxidant agent,has been extensively used in coronary artery disease and other cardiovascular disease.Also,it has been shown that trimetazidine can inhibit myocytes from ischemia reperfusion mediated apoptosis.But it is note clear wheather trimetazidine also inhibit myocytes apoptosis from late reperfusion.We investigated the cardiopro-tection effection and the possible mechanism of trimetazidine in the risk areas during late reperfusion after acute myocardial infarct in canine.
Methods Twenty-four adult dogs were randomly divided into three groups:sham operation group(n=8),late reperfusion group(LR,n=8),and late reperfusion after trimetazidine treatment group(LR+TMZ,n=8).Physiological saline was orally given in the sham operation group and LR group and trimetazidine(2mg·kg~(-1)·d~(-1)) in the LR+TMZ group for fourteen days.Fourteen days later,all dogs were received chest operation and coronary artery was exposed.The late reperfusion of acute myocardial infarction model was made by ligating the coronary for 10 h,followed by reperfusion of 10h.Apoptotic index were detected by TUNEL.The Bcl-2,Bax,Cytochrome C and Apoptosis-inducing factor(AIF) proteins were detected by immunohistochemistry.
Results Compared with LR group,myocardial apoptotic index and the expression of Bax,Cytochrome C and AIF proteins in LR+TMZ were decreased significantly(all P＜0.01),but the expression of Bcl-2 proteins were increased(P＜0.01).Comparing with shame operation group respectively,all indicators were significantly different(p＜0.001).
Conclusion Trimetazidine can decrease cardiomyocyte apoptosis in the risk area during late reperfusion after acute myocardial infarction,which may be related to the increased expression level of Bcl-2 proteins and decreased expression level of Bax, Cytochrome C and AIF proteins.
引文
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2 The effects of tissue plasminogen activator, streptokinase, or both on coronary-artery patency, ventrilcular function, and survival after acute myocardial infarction.The GUSTO Angiographic Investigators. N Engl J Med.1993,329: 1615-1622.
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5 Bellenger NG,Yousef Z,RajapparI K,et al .Infarct zone viability influences ventricular remodelling after late recanalisation of an occluded infarct related artery.Heart,2005,91:478-483.
6 Kim CB,Braunwald E. Potential benefits of late reperfusion of infarcted myocardium. The open artery hypothesis. Circulation. 1993.88:2426-2436.
7 Boyle MP. Weisman HF. Limitation of infarct expansion and ventricular remodeling by late reperfusion. Study oftime coll Pse and mechanism in a rat model.Circulation, 1993,88:2872-2883.
8 Piscione F,Galasso G,De Luca G,et al.Late reopening of an occluded infarct related artery improves left ventrieular function and long term clinical outcome.Heart,2005,91:646-651.
9 YousefZR,Redwood SR,Bucknall C,et al.A randomized trial of delayed intervention after myocardial infaretion:clinical endpoint and echocardiographic data from The Open Artery al(TOAT Study).Circulation,2000,102(Ⅱ Suppl):Ⅱ755.
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