Cardiac Myocyte Apoptosis: Mechanism and Significance

心肌细胞在缺血再灌注损伤和心力衰竭过程中通过凋亡而死亡。来自PI实验室和其他人的大量工作已经证明，通过药理学或遗传手段抑制这种细胞死亡减少了心肌损伤，限制了左心室扩张，改善了收缩功能，并且在某些情况下降低了死亡率。这些研究提供了心肌细胞凋亡是缺血-再灌注损伤和心力衰竭的重要致病机制的初步“概念证明”，并表明抑制细胞死亡可能为这些疾病提供新的治疗靶点。我们现在希望将我们的注意力集中在心肌细胞凋亡的分子调控上。从蠕虫到人类，中央死亡机制一直高度保守，在各种细胞类型之间几乎没有差异。尽管如此，细胞凋亡通常以细胞类型和刺激特异性的方式调节，其基础知之甚少。ARC（具有CARD（半胱天冬酶募集结构域）的凋亡抑制因子）是一种内源性凋亡抑制剂，主要在心肌和骨骼肌中表达。它是迄今为止鉴定的唯一心脏富集的凋亡调节分子。ARC的重要性是强调其有效抑制心肌细胞凋亡引起的各种刺激。然而，关于ARC的作用机制、调节和体内效应知之甚少。我们将开始通过以下目标来定义这些领域：1。确定ARC与凋亡DNA降解机制的新型相互作用和调节机制。2.探讨细胞凋亡过程中ARC降解的机制。3.确定ARC在体内的持续心肌表达是否减轻缺血再灌注损伤引起的心脏结构和功能的急性和慢性异常。总之，这些研究将加深我们对ARC机制和生理学的理解。这些信息可能为利用这种富含心脏的内源性抑制剂来设计缺血性心脏病和心力衰竭的新的特异性治疗方法提供基础。

Cardiac myocytes die by apoptosis during ischemia-reperfusion injury and heart failure. A body of work from the Pl's lab and others has demonstrated that inhibition of this cell death through pharmacologic or genetic means decreases myocardial damage, limits left ventricular dilation, improves contractile function, and in some cases, decreases mortality. These studies provide the initial "proof of concept" that cardiac myocyte apoptosis is an important pathogenic mechanism for ischemia-reperfusion injury and heart failure and suggest that inhibition of cell death may provide a novel therapeutic target for these disorders. We now wish to focus our attention on the molecular regulation of apoptosis specifically in cardiac myocytes. The central death machinery has been highly conserved from worm to human and differs little among various cell types. Despite this, apoptosis is often regulated in a cell type- and stimulus-specific manner, the basis of which is poorly understood. ARC (Apoptosis Repressor with a CARD (caspase recruitment domain)) is an endogenous inhibitor of apoptosis that is expressed primarily in cardiac and skeletal muscle. It is the only cardiac-enriched apoptosis regulatory molecule identified to date. ARC's importance is underscored by its potent inhibition of cardiac myocyte apoptosis elicited by diverse stimuli. Little is known, however, about ARC's mechanism of action, regulation, and in vivo effects. We will begin to define these areas through the following aims: 1. To determine the mechanism of ARC's novel interactions with and regulation of the apoptotic DNA degradation machinery. 2. To determine the mechanism of ARC degradation during apoptosis. 3. To determine whether persistent myocardial expression of ARC in vivo attenuates acute and chronic abnormalities in cardiac structure and function due to ischemia-reperfusion injury. Taken together, these studies will deepen our mechanistic and physiological understanding of ARC. This information may provide the basis for strategies to exploit this cardiac-enriched endogenous inhibitor to design novel and specific therapies for ischemic heart disease and heart failure.