Bcl-2 overexpression corrects mitochondrial defects and ameliorates inherited desmin null cardiomyopathy.
Bcl-2 overexpression corrects mitochondrial defects and ameliorates inherited desmin null cardiomyopathy.
复制标题
Bcl-2 过度表达可纠正线粒体缺陷并改善遗传性结蛋白缺失心肌病。
DOI：
10.1073/pnas.0303202101
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发表时间：
2004
影响因子：
11.1
通讯作者：
Capetanaki,Yassemi
中科院分区：
文献类型：
--
作者：
Weisleder,Noah;Taffet,GeorgeE;Capetanaki,Yassemi
心肌病和心力衰竭的标志之一是明显的和进行性的心肌细胞死亡。了解心肌细胞死亡的机制是心脏病治疗的一个重要课题。缺乏结蛋白（中间丝基因家族的肌肉特异性成员）的小鼠会发生以广泛的心肌细胞死亡、纤维化、钙化和最终心力衰竭为特征的心肌病。最早期的超微结构缺陷见于线粒体。在本研究中，我们已经证明，这些线粒体异常是所观察到的心肌病的主要原因，这些缺陷可以通过过度表达bcl-2在结蛋白无效的心脏得到改善。在结蛋白缺失的心脏中过表达bcl-2导致线粒体缺陷的纠正，减少心肌纤维化病变的发生，防止心脏肥大，恢复心肌细胞超微结构，并显着改善心脏功能。此外，我们发现结蛋白的缺失也降低了线粒体抵抗钙暴露的能力，这种缺陷可以通过bcl-2过表达部分恢复。这些结果表明，结蛋白在保护线粒体免受钙暴露中具有独特的功能，这可以通过bcl-2的过表达来部分挽救。我们发现，bcl-2心脏基因的过表达对遗传性心肌病有显著的改善作用，揭示了bcl-2基因和家族中其他基因作为多种类型心脏病（包括遗传性心脏病）治疗药物的潜力。
One of the hallmarks of cardiomyopathy and heart failure is pronounced and progressive cardiomyocyte death. Understanding the mechanisms involved in cardiomyocyte cell death is a topic of great interest for treatment of cardiac disease. Mice null for desmin, the muscle-specific member of the intermediate filament gene family, develop cardiomyopathy characterized by extensive cardiomyocyte death, fibrosis, calcification, and eventual heart failure. The earliest ultrastructural defects are observed in mitochondria. In the present study, we have demonstrated that these mitochondrial abnormalities are the primary cause of the observed cardiomyopathy and that these defects can be ameliorated by overexpression of bcl-2 in desmin null heart. Overexpression of bcl-2 in the desmin null heart results in correction of mitochondrial defects, reduced occurrence of fibrotic lesions in the myocardium, prevention of cardiac hypertrophy, restoration of cardiomyocyte ultrastructure, and significant improvement of cardiac function. Furthermore, we have found that loss of desmin also diminishes the capacity of mitochondria to resist exposure to calcium, a defect that can be partially restored by bcl-2 overexpression. These results point to a unique function for desmin in protection of mitochondria from calcium exposure that can be partially rescued by overexpression of bcl-2. We show that bcl-2 cardiac overexpression has provided significant improvement of an inherited form of cardiomyopathy, revealing the potential forbcl-2, and perhaps other genes in the family, as therapeutic agents for heart disease of many types, including inherited forms.