Endothelial Mechanism In RIPC

RIPC 中的内皮机制

• 批准号: 9900065
• 负责人: KUMUDA C DAS
• 金额: $ 48.39万
• 依托单位: TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9900065
• 关键词: Acute; Adult; Antioxidants; Apoptosis; Area; Arteries; Biochemical; Biological Assay; Blood flow; Cardiac Myocytes; Cardiomyopathies; Clinical; Coronary; Coronary Circulation; Coronary artery; Data; Development; Distal; ERBB2 gene; Echocardiography; Endothelial Cells; Endothelium; Gastrocnemius Muscle; Generations; Grx1 protein; Heart; Infarction; Injury; Ischemia; Ischemic Preconditioning; Ligation; Mediating; Methodology; Mitochondria; Molecular; Mus; Muscle Cells; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardial perfusion; Myocardium; Myography; Nature; Neuregulins; Organ; Oxidation-Reduction; Pathway interactions; Production; Protein Tyrosine Kinase; Proteins; Reperfusion Injury; Reperfusion Therapy; Research; Risk; Role; Severities; Signal Transduction; Superoxides; TXN gene; Testing; Time; Virus; base; cardioprotection; conditional knockout; coronary perfusion; effective intervention; endothelial dysfunction; erbB-2 Receptor; femoral artery; improved; mouse model; novel; p38 Mitogen Activated Protein Kinase; preconditioning; pressure; prevent; protective factors; receptor; release factor

Remote ischemic preconditioning (RIPC) is a clinically effective and non-invasive ischemia-reperfusion (I/R) of a remote organ that provides significant protection against more acute I/R. However, the specific protective factor released by RIPC or the mechanism of RIPC-mediated protection remains elusive so far. Further, the understanding by which the RIPC released factor confers protection to the heart in I/R remains unclear. We have identified Neuregulin (Nrg1β) as one of the RIPC factors that is required for conferring protection to the myocardium in I/R. Our proposed studies will uncover and endothelial mechanism that RIPC-mediated Nrg1β utilizes to provide protection in I/R injury. We will test the hypothesis that RIPC-mediated release of Nrg1β protects coronary endothelial dysfunction by interacting with its receptor ErbB2 expressed in endothelial cells, and this endothelial Nrg1β-ErbB2 interaction induces survival signaling resulting in protection against myocardial ischemia-reperfusion injury. Our hypothesis is novel and intriguing as endothelial Nrg1β is believed to interact with ErbB2 expressed on cardiomyocytes. Our studies will investigate for the first time the role of Nrg1β-ErbB2 in the coronary endothelium that elicits survival pathway to protect myocardium in I/R. In our aim 1, we will determine the mechanism of RIPC mediated release of Nrg1β that is required for protection against MI; Aim 2) we will determine mitochondrial redox mechanism induced due to protection ErbB2 degradation and its role in protection against coronary endothelial dysfunction due to I/R; Aim 3) the role of RIPC –mediated rescue of ErbB2 and resultant decrease in ROS in protection against endothelial dysfunction, myocardial I/R will be determined. We will use novel mouse model with specific deletion of ErbB2 in the endothelial cells to understand the specific role of endothelial ErbB2 in RIPC-dependent protection of myocardium in I/R. We will use state-of-the art experimental methodology such as proximity ligation assays, pressure and wire myography, echocardiography and molecular and biochemical approaches to delineate the precise role of RIPC-mediated Nrg1β in protection against MI.

远程缺血预处理（RIPC）是一种临床有效的、无创的 远端器官的缺血-再灌注（I/R），提供显著的保护， 急性I/R。然而，由RIPC释放的特异性保护因子或 RIPC介导的保护机制至今仍不清楚。此夕h 了解RIPC释放因子对I/R心脏的保护作用 仍不清楚我们已经确定神经调节蛋白（Nrg 1 β）是RIPC因子之一， 在I/R中对心肌给予保护是必需的。我们建议的研究将 揭示RIPC介导的Nrg 1 β用于提供 I/R损伤的保护。我们将检验RIPC介导的Nrg 1 β释放的假设， 通过与ErbB 2受体相互作用保护冠状动脉内皮功能障碍 在内皮细胞中表达，这种内皮Nrg 1 β-ErbB 2相互作用诱导 存活信号传导导致对心肌缺血-再灌注损伤的保护。 我们的假设是新颖和有趣的，因为内皮Nrg 1 β被认为与 ErbB 2在心肌细胞上表达。我们的研究将首次调查 Nrg 1 β-ErbB 2在增强冠状动脉内皮细胞存活通路中的作用 I/R心肌在我们的目标1中，我们将确定RIPC介导的机制， Nrg 1 β的释放是预防MI所需的;目的2）我们将确定 线粒体氧化还原机制诱导由于保护ErbB 2降解及其 在I/R引起的冠状动脉内皮功能障碍中的保护作用;目的3） RIPC介导的ErbB 2的拯救和由此产生的ROS减少在抗 将确定内皮功能障碍、心肌I/R。我们将使用新颖的鼠标 内皮细胞中ErbB 2特异性缺失的模型以了解特异性 内皮细胞ErbB 2在RIPC依赖的I/R心肌保护中的作用我们将 使用现有技术的实验方法如邻位连接测定， 压力和钢丝肌造影，超声心动图，分子和生化 描述RIPC介导的Nrg 1 β在抗肿瘤保护中的确切作用的方法 MI.