Role of VCP in coronary ischemic injury

VCP在冠状动脉缺血性损伤中的作用

• 批准号: 9920883
• 负责人: Gangjian Qin
• 金额: $ 65.12万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-19 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9920883
• 关键词: ATP phosphohydrolase; Acute myocardial infarction; Apoptosis; Cardiac; Cardiac Myocytes; Cause of Death; Cell Death; Cell Membrane Permeability; Chimeric Proteins; Clinical; Complex; Coronary; Coronary Arteriosclerosis; Coronary artery; Cytoprotection; Data; Dependovirus; Development; Dominant-Negative Mutation; Down-Regulation; Gold; Heart; Heart Diseases; Impairment; In Vitro; Infarction; Injury; Ischemia; Ischemic Preconditioning; Knock-out; Lead; Mediating; Mediator of activation protein; Methods; Mitochondria; Mitochondrial Proteins; Molecular; Molecular Chaperones; Mus; Myocardial; Myocardial Infarction; Myocardial Ischemia; N-terminal; NOS2A gene; Pathway interactions; Peptides; Physiological; Proteins; Reperfusion Injury; Reperfusion Therapy; Research; Role; SKIL gene; Series; Serotyping; Signal Transduction; Sirolimus; Stress; Techniques; Testing; Therapeutic; Transcription Coactivator; Transgenic Mice; United States; cardioprotection; clinically relevant; coronary artery occlusion; experimental study; heart function; heart preservation; in vivo; injured; knock-down; mitochondrial membrane; mouse model; novel; novel therapeutic intervention; novel therapeutics; overexpression; oxidative damage; preservation; protein expression; therapeutic effectiveness; valosin-containing protein

Project Summary Coronary artery heart disease (CAD) is the leading cause of death in the United States. Although pre-ischemic preconditioning (IPC) has been accepted as the "gold standard" method of cardioprotection against coronary ischemic injury; its application remains difficult in the clinical setting because of the requirement of triggering episodes of coronary ischemia reperfusion. Thus, understanding the molecular adaptations induced by IPC is of paramount importance and will help developing novel therapy. Recently, we found that the valosin- containing protein (VCP), an ATPase-associated protein, previously uncharacterized in the heart, is a key mediator of IPC-induced cardiac protection. Specifically, we found that VCP is upregulated in the IPC hearts, and that overexpression of VCP protects cardiomyocytes from the stress-induced apoptosis in vitro and dramatically reduces the infarct size of coronary ischemic injury in vivo, as effective as those conferred by the IPC. Additionally, we found that VCP expression in cardiomyocytes leads to accumulation and activation of the inducible nitric oxide synthase (iNOS) in mitochondria and S-Nitrosylation (SNO) of mitochondrial proteins. We also found that VCP expression leads to activation of the target of rapamycin complex 2 (mTORC2) and mTORC2-dependent signaling. Furthermore, we have identified a regulatory N-domain of VCP that is essential for VCP-mediated cyto-protection. Collectively, our data may have discovered a previously unrecognized role of VCP in cardiac protection and suggests that VCP is a potential novel candidate for therapy of CAD. However, despite these exciting preliminary findings, the physiological significance of VCP in the protection of coronary ischemic injury has not been exquisitely established, and the underlying molecular mechanisms by which VCP mediates mTOCR2 activation and by which VCP/mTORC2 signaling leads to iNOS mitochondrial translocation and function have been largely unknown. Our central hypothesis is that VCP is a potent mediator of cardioprotection against coronary ischemic injury; it promotes cardiac survival by activating mTORC2 and mTORC2-mediated iNOS mitochondrial translocation, leading to preservation of mitochondrial function and enhancement of myocardial tolerance to coronary ischemic injury, We will test our central hypothesis by a comprehensive set of experiments under two specific aims. Under Aim 1 we will define the physiological significance and therapeutic potential of VCP in coronary ischemic injury in mice. Under Aim 2, we will determine the molecular mechanisms by which VCP promotes mTORC2 activation and iNOS mitochondrial translocation and cardiomyocyte survival. We expect that this study will advance the field by establishing the protective role of VCP in coronary ischemic injury and opening new avenues into research for better therapy of CAD.

项目摘要 冠状动脉心脏病（CAD）是美国的主要死因。虽然缺血前 预处理（IPC）已被公认为心脏保护的“金标准”方法， 缺血性损伤;由于需要触发，其在临床环境中的应用仍然困难 冠状动脉缺血再灌注发作。因此，理解IPC诱导的分子适应是 这将有助于开发新的治疗方法。最近，我们发现瓦洛辛- 包含蛋白质（VCP）是一种ATP酶相关蛋白质，以前在心脏中未被表征，这是一个关键 介导IPC诱导的心脏保护。具体来说，我们发现VCP在IPC心脏中上调， VCP的过表达在体外可保护心肌细胞免受应激诱导的凋亡， 显著降低体内冠状动脉缺血性损伤的梗死面积，与 IPC。此外，我们发现心肌细胞中VCP的表达导致了心肌细胞中VCP的积累和激活。 线粒体中的诱导型一氧化氮合酶（iNOS）和线粒体蛋白质的S-亚硝基化（SNO）。我们 还发现VCP表达导致雷帕霉素复合物2（mTORC 2）的靶点活化， mTORC 2依赖性信号传导。此外，我们已经确定了VCP的调节N-结构域， 用于VCP介导的细胞保护。总的来说，我们的数据可能发现了一个以前未被认识的角色， 提示VCP是一种潜在的治疗冠心病的新药物。 然而，尽管有这些令人兴奋的初步发现，VCP在保护 冠状动脉缺血性损伤尚未得到精确的确定，其潜在的分子机制是 VCP介导mTOCR 2激活，VCP/mTORC 2信号传导导致iNOS线粒体 易位和功能在很大程度上是未知的。我们的中心假设是，VCP是一个有效的调解人 对冠状动脉缺血性损伤的心脏保护;它通过激活mTORC 2促进心脏存活， mTORC 2介导的iNOS线粒体易位，导致线粒体功能的保留， 增强心肌对冠状动脉缺血性损伤的耐受性，我们将通过以下方法检验我们的中心假设： 在两个具体目标下的综合实验。在目标1下，我们将定义生理 VCP对小鼠冠状动脉缺血性损伤意义及治疗潜力根据目标2，我们将 确定VCP促进mTORC 2激活和iNOS线粒体的分子机制 易位和心肌细胞存活。我们希望这项研究将通过建立 VCP在冠状动脉缺血性损伤中的保护作用，并为更好地治疗 CAD.