Role of VCP in coronary ischemic injury

VCP在冠状动脉缺血性损伤中的作用

基本信息

批准号：
10242622
负责人：
Hongyu Qiu
金额：
$ 63.42万
依托单位：
GEORGIA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-19 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10242622
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 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 effectiveness evaluation experimental study heart function heart preservation in vivo ischemic injury knock-down mitochondrial membrane mouse model novel novel therapeutic intervention novel therapeutics overexpression oxidative damage preservation protein expression therapeutic effectiveness valosin-containing protein

项目摘要

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）是美国死亡的主要原因。虽然是缺血性的预处理（IPC）已被接受为针对冠状动脉的“金标准”方法缺血性损伤；由于需要触发，其应用程序在临床环境中仍然很困难冠状动脉缺血再灌注的发作。因此，了解IPC诱导的分子适应为至关重要，将有助于发展新的疗法。最近，我们发现valosin- 含有蛋白质（VCP），一种以前未在心脏中未表征的ATPase相关蛋白是钥匙 IPC诱导的心脏保护介质。具体而言，我们发现VCP在IPC心脏中被上调， VCP的过表达可保护心肌细胞免受压力诱导的体外凋亡的影响大大降低了体内冠状动脉缺血损伤的梗塞大小，与由 IPC。此外，我们发现心肌细胞中的VCP表达导致积累和激活线粒体蛋白的线粒体和S-亚硝基化（SNO）中的诱导一氧化氮合酶（iNOS）。我们还发现VCP表达会导致雷帕霉素复合物2（MTORC2）和 MTORC2依赖性信号传导。此外，我们已经确定了VCP的调节n域，这是必不可少的用于VCP介导的细胞保护。总的来说，我们的数据可能已经发现了先前未认可的角色 VCP在心脏保护方面的作用，并表明VCP是CAD治疗的潜在新型候选者。然而，尽管有这些令人兴奋的初步发现，但VCP在保护保护方面的生理意义冠状动脉缺血性损伤尚未得到明确的确定，并且通过 VCP介导mToCR2激活，并通过其中VCP/MTORC2信号导致iNOS线粒体易位和功能在很大程度上未知。我们的中心假设是VCP是一个有效的调解人针对冠状动脉缺血损伤的心脏保护；它通过激活mtorc2和 MTORC2介导的iNOS线粒体易位，导致线粒体功能和增强对冠状动脉缺血损伤的心肌耐受性，我们将通过在两个具体目标下进行的全面实验集。在AIM 1下，我们将定义生理 VCP在小鼠冠状动脉缺血性损伤中的显着性和治疗潜力。在AIM 2下，我们将确定VCP促进MTORC2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，并将新的途径开放给研究，以更好地治疗卡德。