MITOCHONDRIAL STRESS PROTEINS AND CARDIOPROTECTION

线粒体应激蛋白和心脏保护

• 批准号: 6192642
• 负责人: RUBEN MESTRIL
• 金额: $ 29.1万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-15 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6192642
• 关键词: adenosine triphosphate; apoptosis; cardiac myocytes; cysteine endopeptidases; cytoprotection; genetically modified animals; heat shock proteins; laboratory mouse; laboratory rat; mitochondria; molecular assembly /self assembly; molecular chaperones; myocardial ischemia /hypoxia; newborn animals; oxidative phosphorylation

DESCRIPTION (the applicant's description verbatim): Although, there has been much progress in the management of myocardial ischemia, myocardial infarction remains the major cause of death in the U.S. Acute myocardial infarction is commonly caused by thrombosis or occlusion of the coronary arteries which feed the left ventricle of the heart. The absence of blood flow to the cardiac muscle results in severe cellular damage that eventually compromises the muscle's ability to contract. This is due, among other things, to the limitation in oxygen delivery that reduces mitochondrial oxidative phosphorylation and contributes to the reduction of intracellular ATP levels. Research has shown that the inability of the mitochondria to self-repair following restoration of blood flow may be a crucial event leading to myocardial cell death. Recent studies show that part of this myocardial cell death is through apoptosis. One of the main protein assembly structures in the mitochondria is made up by the molecular chaperones or mitochondrial stress proteins. These proteins are known as the mitochondrial hsp70, hsp60 and hsp10. These last two proteins form the chaperonin complex which together with ATP is involved in the assembly of the majority of the mitochondrial proteins including the enzyme complexes involved in oxidative phosphorylation. We have found that increased expression of the hsp60 and hsp10 in cardiomyocytes renders the myocyte significantly tolerant to ischemic injury Interestingly, we find that part of this protection effect of overexpressing the mitochondrial stress proteins is due to a reduction in the amount of apoptosis induced by ischemia/reperfusion We find that the protective effect by hsp60 and hsp10 seems to be mediated by their binding to cytochrome c and the retention of this last protein inside the mitochondria and therefore potentially decreasing the activation of the caspases, the main culprits of apoptosis We therefore believe that a better understanding of the mechanism of how the mitochondrial hsps protect the cardiomyocyte during ischemia/reperfusion injury will permit us to harness this endogenous defense mechanism

描述（申请人的逐字描述）：尽管如此， 心肌缺血、心肌梗死的治疗取得很大进展 急性心肌梗塞仍然是美国主要死亡原因 通常由血栓形成或供血的冠状动脉闭塞引起 心脏的左心室。缺乏流向心脏的血液 肌肉会导致严重的细胞损伤，最终损害 肌肉的收缩能力。除其他外，这是由于 氧输送的限制会减少线粒体的氧化 磷酸化并有助于降低细胞内 ATP 水平。 研究表明线粒体无法自我修复 血流恢复后可能是导致 心肌细胞死亡。最近的研究表明，这种心肌细胞的一部分 死亡是通过细胞凋亡。蛋白质的主要组装结构之一 线粒体由分子伴侣或线粒体应激组成 蛋白质。这些蛋白质被称为线粒体 hsp70、hsp60 和 hsp10。 最后两种蛋白质形成伴侣蛋白复合物，与 ATP 一起形成 参与大多数线粒体蛋白质的组装 包括参与氧化磷酸化的酶复合物。我们有 发现心肌细胞中 hsp60 和 hsp10 的表达增加 使肌细胞对缺血性损伤具有显着的耐受性 发现过度表达线粒体的部分保护作用 应激蛋白是由于应激蛋白诱导的细胞凋亡数量减少所致 缺血/再灌注 我们发现 hsp60 和 hsp10 的保护作用 似乎是通过它们与细胞色素 c 的结合以及该细胞色素 c 的保留来介导的 线粒体内的最后一个蛋白质，因此可能减少 半胱天冬酶的激活，细胞凋亡的罪魁祸首因此我们相信 更好地了解线粒体热休克蛋白的机制 在缺血/再灌注损伤期间保护心肌细胞将使我们能够 利用这种内源性防御机制