冠状动脉微栓塞致心肌细胞凋亡及心功能损伤的死亡受体途径研究
摘要
目的探讨大鼠冠状动脉微栓塞(Coronary Microembolization CME)后心肌细胞凋亡及其死亡受体凋亡途径激活的动态变化规律。
方法采用夹闭升主动脉经左室注射42μM微球(3×104/ml ,3000个)建立大鼠冠状动脉微栓塞模型。设为微栓塞组(CME组,n=63);以注射生理盐水为假手术组(S组,n=55)。每组存活大鼠按不同观察时间点随机分为0h、3h、6h、12h、24h组,每组10例。组织病理切片HE及HBFP染色进行梗死区域测量;应用心脏超声检测心功能指标;末端脱氧核糖核酸转移酶介导的dUTP切口末端标记技术(TUNEL)检测心肌细胞凋亡; Western blot检测活化Caspase-3及Caspase-8的表达。
结果CME组3h、6h、12h、24h时间点均可见微梗死灶,分别为(7.98±2.58)%、(8.32±3.27)%、(8.40±3.41)%、(8.52±3.76)%,但各时间点之间的微梗死面积比较无统计学差异(均P>0.05);CME前,大鼠的平均LVEF为87.69±4.41%,CME后,除0h组外其余时间点LVEF均较S组明显降低(均P<0.05)。伴随着LVEF显著下降,心脏超声表现为左室短轴缩短率(FS)和心排血量(CO)下降及左室舒张期末径(LVEDd)增加(均P<0.05);与假手术组比较,微栓塞组各时间点的心肌细胞凋亡指数均显著升高(P<0.05),凋亡主要分布在微梗死区及其边缘区,冠状动脉微栓塞组各时间点,以6h组的凋亡指数最高(P<0.05),12h组开始下降; Western blot结果显示细胞凋亡过程中最主要的终末剪切酶caspase-3和死亡受体凋亡通路的关键蛋白Caspase-8的表达都是在3h开始升高,6h达高峰(P<0.05),12h开始表达减少,24h已显著下降。与相应S组比较,除0h组外CME各组caspase-3、Caspase-8的表达均显著升高(P<0.05)
结论冠状动脉微栓塞致心肌细胞凋亡显著增加,且具有动态变化规律。死亡受体凋亡途径可能是冠状动脉微栓塞致心肌细胞凋亡及其心功能损伤的重要机制之一。
Objective To investigate the dynamic change of cardiomyocyte apoptosis and the role of death receptor apoptotic pathway after coronary microembolization(CME) in rats .
Methods Coronary microembolization models were produced by injection of 42μm microspheres(3×104/ml, 3000) into the left ventricle while occlusion the ascending aorta. The Sprague-Dawley rats were randomly divided into the sham group(S group, n=55), coronary microembolization group(CME group, n=63), The survivors were randomly into 0h、3h、6 h、12 h、24h five groups post CME (n=10). Echocardiography was used to evaluate heart function. Sections of myocardium were stained with hematoxylin-eosin and hematoxylin-basic fuchsin-picric acid for detecting infarct areas. Cardiomyocyte apoptosis was detected with in stiu terminal deoxynucleotidyl transferase (TdT)–mediated dUTP nick end-labeling (TUNEL staining).The expression of caspase-3 and caspase-8 was detected with Western blot analysis.
Results The infarct sizes were similar in three hour, six hour, 12 hour, and 24 hour CME groups (P>0.05). The average left ventricle ejection fraction(LVEF) in the normal control group was 87.69±4.41%. Compared with sham-operated group. The LVEF of CME group were markedly decreased( P<0.05 ) expect 0h CME group. Echocardiography showed that Left ventricular ejection fraction(LVEF)、short axis fractional shortening(FS) and Cardiac output(CO) decreased, but Left ventricular end-diastolic diameter increased after CME. The apoptosis index in CME group were significantly increased at each time point comparing to sham group(P<0.05) expect 0h CME group, whose peak level showed up at the 6h time point but markedly decreased at the 12h time point. Apoptotic cardiomyocytes were found mainly in the border zones and the infarct foci. The relative expression of caspase-3 and caspase-8 in CME group both increased at 3h post CME, peaked at 6h post CME(P<0.05), and then gradually decreased, remarkably low at 24h. Compared with sham-operated group, the relative levels of caspase-3 and caspase-8 in CME group were significantly increased(P<0.05) expect 0h CME group.
Conclusion The amount of cardiomyocytes apoptosis was significantly increased after coronary microembolization, with dynamic changes in the law. Death receptor apoptotic pathway may be involved in coronary microembolization-induced myocardial apoptosis. Cardiomyocytes apoptosis may be one of the important mechanisms of myocardial injury after coronary microembolization in rats.
方法采用夹闭升主动脉经左室注射42μM微球(3×104/ml ,3000个)建立大鼠冠状动脉微栓塞模型。设为微栓塞组(CME组,n=63);以注射生理盐水为假手术组(S组,n=55)。每组存活大鼠按不同观察时间点随机分为0h、3h、6h、12h、24h组,每组10例。组织病理切片HE及HBFP染色进行梗死区域测量;应用心脏超声检测心功能指标;末端脱氧核糖核酸转移酶介导的dUTP切口末端标记技术(TUNEL)检测心肌细胞凋亡; Western blot检测活化Caspase-3及Caspase-8的表达。
结果CME组3h、6h、12h、24h时间点均可见微梗死灶,分别为(7.98±2.58)%、(8.32±3.27)%、(8.40±3.41)%、(8.52±3.76)%,但各时间点之间的微梗死面积比较无统计学差异(均P>0.05);CME前,大鼠的平均LVEF为87.69±4.41%,CME后,除0h组外其余时间点LVEF均较S组明显降低(均P<0.05)。伴随着LVEF显著下降,心脏超声表现为左室短轴缩短率(FS)和心排血量(CO)下降及左室舒张期末径(LVEDd)增加(均P<0.05);与假手术组比较,微栓塞组各时间点的心肌细胞凋亡指数均显著升高(P<0.05),凋亡主要分布在微梗死区及其边缘区,冠状动脉微栓塞组各时间点,以6h组的凋亡指数最高(P<0.05),12h组开始下降; Western blot结果显示细胞凋亡过程中最主要的终末剪切酶caspase-3和死亡受体凋亡通路的关键蛋白Caspase-8的表达都是在3h开始升高,6h达高峰(P<0.05),12h开始表达减少,24h已显著下降。与相应S组比较,除0h组外CME各组caspase-3、Caspase-8的表达均显著升高(P<0.05)
结论冠状动脉微栓塞致心肌细胞凋亡显著增加,且具有动态变化规律。死亡受体凋亡途径可能是冠状动脉微栓塞致心肌细胞凋亡及其心功能损伤的重要机制之一。
Objective To investigate the dynamic change of cardiomyocyte apoptosis and the role of death receptor apoptotic pathway after coronary microembolization(CME) in rats .
Methods Coronary microembolization models were produced by injection of 42μm microspheres(3×104/ml, 3000) into the left ventricle while occlusion the ascending aorta. The Sprague-Dawley rats were randomly divided into the sham group(S group, n=55), coronary microembolization group(CME group, n=63), The survivors were randomly into 0h、3h、6 h、12 h、24h five groups post CME (n=10). Echocardiography was used to evaluate heart function. Sections of myocardium were stained with hematoxylin-eosin and hematoxylin-basic fuchsin-picric acid for detecting infarct areas. Cardiomyocyte apoptosis was detected with in stiu terminal deoxynucleotidyl transferase (TdT)–mediated dUTP nick end-labeling (TUNEL staining).The expression of caspase-3 and caspase-8 was detected with Western blot analysis.
Results The infarct sizes were similar in three hour, six hour, 12 hour, and 24 hour CME groups (P>0.05). The average left ventricle ejection fraction(LVEF) in the normal control group was 87.69±4.41%. Compared with sham-operated group. The LVEF of CME group were markedly decreased( P<0.05 ) expect 0h CME group. Echocardiography showed that Left ventricular ejection fraction(LVEF)、short axis fractional shortening(FS) and Cardiac output(CO) decreased, but Left ventricular end-diastolic diameter increased after CME. The apoptosis index in CME group were significantly increased at each time point comparing to sham group(P<0.05) expect 0h CME group, whose peak level showed up at the 6h time point but markedly decreased at the 12h time point. Apoptotic cardiomyocytes were found mainly in the border zones and the infarct foci. The relative expression of caspase-3 and caspase-8 in CME group both increased at 3h post CME, peaked at 6h post CME(P<0.05), and then gradually decreased, remarkably low at 24h. Compared with sham-operated group, the relative levels of caspase-3 and caspase-8 in CME group were significantly increased(P<0.05) expect 0h CME group.
Conclusion The amount of cardiomyocytes apoptosis was significantly increased after coronary microembolization, with dynamic changes in the law. Death receptor apoptotic pathway may be involved in coronary microembolization-induced myocardial apoptosis. Cardiomyocytes apoptosis may be one of the important mechanisms of myocardial injury after coronary microembolization in rats.
引文
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[2] Ronen Jaffe, Thierry Charron, Geoffrey Puley, et al Microvascular Obstruction and the No-Reflow Phenomenon After Percutaneous Coronary Intervention[J]. Circulation, Jun 2008; 117(24): 3152 - 3156.
[3] Itsuro Morishima, Takahito Sone, Kenji Okumura, et al Angiographic no-reflow phenomenon as a predictor of adverse long-term outcome in patients treated with percutaneous transluminal coronary angioplasty for first acute myocardial infarction[J]. J Am Coll Cardiol, 2000; 36(4):1202-1209.
[4] Waksman R, Douglas JS, Jr., Scott NA, et al. Distal embolization is common after directional atherectomy in coronary arteries and saphenous vein grafts[J]. Am Heart J, 1995; 129(3): 430-435.
[5] Grube E, Schofer JJ, Webb J, et al. Evaluation of a balloon occlusion and aspiration system for protection from distal embolization during stenting in saphenous vein grafts[J]. Am J Cardiol, 2002; 89(8): 941-945.
[6]李浪,刘唐威,Tan Hauycheem, Lim YeanTeng. Primary coronary angioplasty with the use of distal embolization protection device in acute myocardial infarction patients[J].中华急诊医学杂志,2004,13(9):1-4.
[7]李浪,Tan Hauycheem, Teo SweeGuan, Lim YeanTeng.远端保护装置在冠状动脉旁路移植术后大隐静脉桥病变介入治疗的临床效果[J].中华心血管病杂志,2004,32(7):614-617.
[8]李浪,Tan Hauycheem, Teo SweeGuan, Lim YeanTeng.远端血栓保护装置在经皮冠状动脉介入治疗中的应用[J].中华心血管病杂志,2004,32(1):44-45.
[9]李浪,Tan Hauycheem, Lim YeanTeng.远端血栓保护装置PercuSurge在急性冠脉综合征经皮冠脉介入治疗中的应用[J].中国介入心血管病杂志,2004,12(4):224-227.
[10]李浪,Tan Hauycheem, Lim YeanTeng.远端血栓保护装置在冠状动脉介入治疗中的应用[J].中国循环杂志,2003,18(3):235-237.
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