Endothelial Mechanism In RIPC

RIPC 中的内皮机制

• 批准号: 10381711
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10381711
• 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.

远程缺血预适应(RIPC)是一种临床有效、无创的 远程器官的缺血-再灌注(I/R)，可提供显著的保护 然而，RIPC或RIPC释放的特定保护因素 到目前为止，RIPC介导的保护机制仍不清楚。此外， 了解RIPC释放的因子在I/R中对心脏的保护作用 目前仍不清楚。我们已将神经调节蛋白(Nrg1β)确定为RIPC因子之一 对I/R心肌具有保护作用。我们建议的研究将 RIPC介导的Nrg1β利用揭示和内皮机制提供 对I/R损伤的保护。我们将检验RIPC介导的Nrg1β释放的假设 通过与受体ErbB2相互作用保护冠状动脉内皮细胞功能障碍 在内皮细胞中表达，这种内皮细胞Nrg1β-erbB2相互作用诱导 存活信号对心肌缺血再灌注损伤的保护作用。 我们的假设是新颖而耐人寻味的，因为内皮细胞Nrg1β被认为与 ERBB2在心肌细胞表达。我们的研究将首次调查 Nrg1β-ErbB2在冠脉内皮细胞诱导存活途径保护中的作用 在我们的目标1中，我们将确定RIPC介导的机制 发布预防心肌梗死所需的NRG1β；目标2)我们将确定 保护ErbB2降解诱导线粒体氧化还原机制及其机制 对缺血/再灌注所致冠状动脉内皮细胞功能障碍的保护作用；目的3) RIPC介导的ErbB2的拯救和由此导致的ROS的降低 内皮功能障碍、心肌I/R将被确定。我们将使用新奇的鼠标 用ErbB2特异性缺失模型了解内皮细胞的特异性 内皮细胞ErbB2在RIPC依赖的I/R心肌保护中的作用 使用最先进的实验方法，如邻近结扎分析， 压力和线状肌图、超声心动图以及分子和生化 确定RIPC介导的Nrg1β在抗病毒中的确切作用的方法 密西西比。