Cardiac Myocyte Apoptosis: Mechanism and Significance

心肌细胞凋亡：机制和意义

• 批准号: 7391573
• 负责人: Richard N Kitsis
• 金额: $ 39.59万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7391573
• 关键词: Acute; Address; Animals; Apoptosis; Apoptosis Inhibitor; Apoptotic; Area; Attention; Attenuated; Cardiac; Cardiac Myocytes; Caspase; Cell Death; Cell Death Inhibition; Cells; Cessation of life; Chronic; Condition; DNA; Disease; Effectiveness; Event; Genetic; Heart; Heart failure; Human; Infarction; Ischemia; Left; Maps; Mediating; Mitochondria; Molecular; Mus; Mutate; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myosin Heavy Chains; Partner in relationship; Pathway interactions; Physiological; Physiological reperfusion; Proteins; Reagent; Regulation; Reperfusion Injury; Reperfusion Therapy; Resistance; Role; Series; Site; Skeletal Muscle; Stimulus; Structure; Testing; Tetanus Helper Peptide; Tetracycline; Tetracyclines; Trans-Activators; Transgenic Mice; Ubiquitin; Ubiquitin-Proteasomal Pathway; Ventricular; Work; base; cell type; concept; design; improved; in vivo; inhibitor/antagonist; mortality; novel; novel therapeutics; programs; protein degradation; size; theories; therapeutic target

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.

心肌细胞在缺血再灌注损伤和心力衰竭期间因细胞凋亡而死亡。 Pl 实验室和其他实验室的大量工作表明，通过药理学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。这些研究提供了初步的“概念证明”，即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，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，中枢死亡机制都高度保守，并且不同细胞类型之间差异不大。尽管如此，细胞凋亡通常以细胞类型和刺激特异性的方式进行调节，但其基础尚不清楚。 ARC（具有 CARD（半胱天冬酶募集结构域）的细胞凋亡抑制因子）是一种内源性细胞凋亡抑制剂，主要在心肌和骨骼肌中表达。它是迄今为止发现的唯一富含心脏的细胞凋亡调节分子。 ARC 的重要性在于它能有效抑制多种刺激引起的心肌细胞凋亡。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.确定细胞凋亡过程中ARC降解的机制。 3.确定ARC在体内持续的心肌表达是否减轻由于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。总而言之，这些研究将加深我们对 ARC 的机制和生理学理解。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针对缺血性心脏病和心力衰竭的新型特异性疗法的策略提供基础。