Role of Bnip3 in Myocardial Ischemia/Reperfusion

Bnip3 在心肌缺血/再灌注中的作用

• 批准号: 7837043
• 负责人: Asa B. Gustafsson
• 金额: $ 5.98万
• 依托单位: SAN DIEGO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2009-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7837043
• 关键词: Acute; Adult; Amino Acid Sequence; Animal Model; Apoptosis; Apoptotic; Autophagocytosis; Autophagosome; Cardiac Myocytes; Caspase; Caspase Inhibitor; Cell Death; Cell Fractionation; Cells; Chronic; Coupled; Cysteine; Data; Development; Family; Goals; Heart; Heart Diseases; Heart failure; Heterodimerization; Homodimerization; Hydrogen Peroxide; Hypoxia; Ischemia; Lead; Life; Mediating; Mitochondria; Molecular; Muscle Cells; Myocardial; Myocardial Ischemia; Myocardium; N-terminal; Neonatal; Outer Mitochondrial Membrane; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Peptide Hydrolases; Peptide Sequence Determination; Play; Production; Protein Family; Proteins; Proteolysis; Reactive Oxygen Species; Regulation; Reperfusion Injury; Reperfusion Therapy; Reporting; Research Personnel; Role; Scanning; Simulate; Site; Staging; Stress; Structure; Transmission Electron Microscopy; Up-Regulation; cell type; cellular imaging; cytochrome c; disulfide bond; in vivo; insight; member; mitochondrial dysfunction; mitochondrial permeability transition pore; new therapeutic target; overexpression; oxidation; prevent; programs; response; sensor

DESCRIPTION (provided by applicant): Cell death by apoptosis is recognized as a major component of ischemia/reperfusion (I/R) injury. Activation of cell death pathways during I/R leads to loss of terminally differentiated cardiac myocytes, thus contributing to the development of heart failure. The Bcl-2 family proteins play an important role in regulating the mitochondrial pathway of apoptosis in the myocardium. BnipS is a pro-apoptotic member of the Bcl-2 family and is localized primarily to the mitochondria in myocardial cells. Overexpression of BnipS leads to mitochondrial dysfunction and cell death in various cell types, including neonatal cardiac myocytes. Elevated levels of BnipS protein have been reported in vivo in animal models of acute ischemia and heart failure. We have found that BnipS is expressed at substantially in the adult myocardium and our preliminary data indicate that BnipS plays a significant role in l/R-mediated cell death by activation of the mitochondrial pathway. Moreover, we have found that overexpression of BnipS causes extensive fragmentation of the mitochondrial network along with upregulation of autophagy, and that BnipS is subjected to proteolysis in cells subjected to hypoxia or simulated I/R. (8). In this proposal, we will explore the hypothesis that BnipS functions as a redox sensor that is activated by increased oxidative stress during I/R, leading to mitochondrial dysfunction and subsequent cell death. This hypothesis will be explored with the following specific aims: 1. Investigate the role of BnipS as a mitochondrial sensor of oxidative stress 2. Define the molecular mechanism(s) by which BnipS mediates mitochondrial fragmentation 3. Elucidate the role of autophagy in BnipS-mediated cell death 4. Characterize the role of BnipS proteolysis in response to I/R Our long-term goal is to understand the pathways that contribute to I/R injury and the results from this proposal will provide new insights into the pathways of apoptosis and their regulation in the heart. Further understanding of how BnipS functions in the heart has the potential to identify new therapeutic targets to treat or prevent heart disease.

描述（由申请人提供）：细胞凋亡导致的细胞死亡被认为是缺血/再灌注（I/R）损伤的主要组成部分。 I/R期间细胞死亡途径的激活导致终末分化的心肌细胞丧失，从而导致心力衰竭的发展。 Bcl-2家族蛋白在调节心肌细胞凋亡的线粒体途径中发挥重要作用。 BnipS 是 Bcl-2 家族的促凋亡成员，主要定位于心肌细胞的线粒体。 BnipS 的过度表达会导致多种细胞类型（包括新生儿心肌细胞）的线粒体功能障碍和细胞死亡。据报道，在急性缺血和心力衰竭的动物模型中，体内 BnipS 蛋白水平升高。我们发现 BnipS 在成体心肌中大量表达，并且我们的初步数据表明 BnipS 通过激活线粒体途径在 L/R 介导的细胞死亡中发挥重要作用。此外，我们发现 BnipS 的过度表达会导致线粒体网络广泛断裂以及自噬上调，并且 BnipS 在缺氧或模拟 I/R 的细胞中会发生蛋白水解。 （8）。在本提案中，我们将探讨这样的假设：BnipS 作为氧化还原传感器，在 I/R 过程中被氧化应激增加激活，导致线粒体功能障碍和随后的细胞死亡。该假设将通过以下具体目标进行探索： 1. 研究 BnipS 作为氧化应激线粒体传感器的作用 2. 定义 BnipS 介导线粒体断裂的分子机制 3. 阐明自噬在 BnipS 介导的细胞死亡中的作用 4. 表征 BnipS 蛋白水解在响应 I/R 中的作用 我们的长期目标是了解 导致 I/R 损伤的途径以及该提案的结果将为细胞凋亡途径及其在心脏中的调节提供新的见解。进一步了解 BnipS 在心脏中的功能有可能确定治疗或预防心脏病的新治疗靶点。