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细胞凋亡而死亡。来自PL实验室和其他实验室的一系列工作已经证明，通过药物或遗传手段抑制这种细胞死亡可以减少心肌损伤，限制左心室扩张，改善收缩功能，在某些情况下，还可以降低死亡率。这些研究为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提供了初步的概念证据，并提示抑制细胞死亡可能为这些疾病提供新的治疗靶点。现在，我们希望将注意力集中在心肌细胞凋亡的分子调控上。中央死亡机制从蠕虫到人类都是高度保守的，在不同类型的细胞之间几乎没有区别。尽管如此，细胞凋亡通常是以一种特定的细胞类型和刺激方式进行调控，其基础还知之甚少。ARC是一种内源性的细胞凋亡抑制因子，主要在心肌和骨骼肌中表达。到目前为止，它是唯一被发现的心脏富含的细胞凋亡调节分子。ARC的重要性因其对不同刺激引起的心肌细胞凋亡的有效抑制而得到强调。然而，人们对ARC的作用机制、调节和体内效应知之甚少。我们将通过以下目标开始定义这些区域：1.确定ARC与凋亡DNA降解机制的新的相互作用和调节的机制。2.探讨ARC在细胞凋亡过程中降解的机制。3.确定体内持续表达ARC是否能减轻因缺血再灌注损伤而引起的急、慢性心脏结构和功能异常。综上所述，这些研究将加深我们对ARC的机制和生理的理解。这一信息可能为开发这种富含心脏的内源性抑制物来设计治疗缺血性心脏病和心力衰竭的新的和特异的疗法提供基础。

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.