Apoptosis in heart failure:: Release of cytochrome c from mitochondria and activation of caspase-3 in human cardiomyopathy
Apoptosis in heart failure:: Release of cytochrome c from mitochondria and activation of caspase-3 in human cardiomyopathy
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DOI：
10.1073/pnas.96.14.8144
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发表时间：
1999-07-06
影响因子：
11.1
通讯作者：
Kharbanda, S
中科院分区：
文献类型：
--
作者：
Narula, J;Pandey, P;Kharbanda, S
细胞凋亡已被证明有助于心肌病中心肌细胞的损失，左心室功能的进行性下降，充血性心力衰竭，因为参与心肌细胞凋亡的分子机制还没有完全了解，我们研究了从接受移植的患者中取出的心脏中的细胞凋亡上游调节因子的生化和超微结构特征。应用电镜和免疫印迹技术对16例心脏移植术后离体心脏线粒体细胞色素c释放和caspase-3活性进行了研究。或来自三个供体心脏的心肌心室组织用作对照，仅在终末期心肌病中观察到细胞凋亡的证据，细胞色素c在衰竭心肌细胞的胞浆、肌原纤维和闰盘附近有明显的蓄积。线粒体细胞色素c的释放与caspase-3的激活及其底物蛋白激酶C δ的裂解有关，但与聚（ADP-核糖）聚合酶无关。相比之下，在用作对照的心脏中没有明显的细胞色素c或半胱天冬酶-3激活的积累。本研究提供了人类心肌病中半胱氨酸蛋白酶的细胞色素c依赖性激活的体内证据。蛋白酶的激活支持肌病过程中的细胞凋亡现象。由于心肌细胞的损失导致心肌功能障碍，是充血性心力衰竭患者不良结局的预测因子，因此目前心肌病中激活的凋亡级联反应的证明可以为新的干预策略提供基础。
Apoptosis has been shown to contribute to loss of cardiomyocytes in cardiomyopathy, progressive decline in left ventricular function,, and congestive heart failure, Because the molecular mechanisms involved in apoptosis of cardiocytes are not, completely understood, we studied the biochemical and ultrastructural characteristics of upstream regulators of apoptosis in hearts explanted from patients undergoing transplantation. Sixteen explanted hearts from patients undergoing heart transplantation were studied by electron microscopy or immunoblotting to detect release of mitochondrial cytochrome c and activation of caspase-3, The hearts explanted from five victims of motor vehicle accidents;or myocardial ventricular tissues from three donor hearts were used as controls, Evidence of apoptosis was observed only in endstage cardiomyopathy, There was significant accumulation of cytochrome c in the cytosol, over myofibrils, and near intercalated discs of cardiomyocytes in failing hearts. The release of mitochondrial cytochrome c was associated with activation of caspase-3 and cleavage of its substrate protein kinase C delta but not poly(ADP-ribose) polymerase. By contrast there was no apparent accumulation of cytosolic cytochrome c or caspase-3 activation in the hearts used as controls, The present study provides irt vivo evidence of cytochrome c-dependent activation of cysteine proteases in human cardiomyopathy. Activation of proteases supports the phenomenon of apoptosis in myopathic process. Because loss of myocytes contributes to myocardial dysfunction and is a predictor of adverse outcomes in the patients with congestive heart failure, the present demonstration of an activated apoptotic cascade in cardiomyopathy could-provide the basis for novel interventional strategies.