The Role of Tissue Factor: FVIIa-PAR-2 Signaling in Heart Ischemia/Reperfusion

组织因子的作用：FVIIa-PAR-2 信号传导在心脏缺血/再灌注中的作用

• 批准号: 8039581
• 负责人: RAFAL L PAWLINSKI
• 金额: $ 36.42万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-15 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8039581
• 关键词: Attenuated; Blood Coagulation Factor; Cardiac; Cardiac Myocytes; Cells; Cicatrix; Clinical; Coagulation Process; Collagen; Complex; Data; Development; Extravasation; Factor VIIa; Fibrin split products; Fibrosis; Functional disorder; Generations; Goals; Growth; Heart; Heart failure; Infarction; Inflammation; Inflammatory; Lead; Modeling; Morbidity - disease rate; Myocardial Infarction; Myocardial Ischemia; Myocardial tissue; Myocardium; Outcome; Oxidative Stress; PAR-1 Receptor; PAR-2 Receptor; Pathologic; Pathway interactions; Play; Production; Property; Reactive Oxygen Species; Reperfusion Injury; Reperfusion Therapy; Role; Signal Transduction; Thrombin; Thromboplastin; Time; Tissues; Western World; chemokine; cytokine; heart function; improved; in vivo; injured; mortality; mouse model; myocardial infarct sizing; neutrophil; novel strategies; prevent; tool; Attenuated; Blood Coagulation Factor; Cardiac; Cardiac Myocytes; Cells; Cicatrix; Clinical; Coagulation Process; Collagen; Complex; Data; Development; Extravasation; Factor VIIa; Fibrin split products; Fibrosis; Functional disorder; Generations; Goals; Growth; Heart; Heart failure; Infarction; Inflammation; Inflammatory; Lead; Modeling; Morbidity - disease rate; Myocardial Infarction; Myocardial Ischemia; Myocardial tissue; Myocardium; Outcome; Oxidative Stress; PAR-1 Receptor; PAR-2 Receptor; Pathologic; Pathway interactions; Play; Production; Property; Reactive Oxygen Species; Reperfusion Injury; Reperfusion Therapy; Role; Signal Transduction; Thrombin; Thromboplastin; Time; Tissues; Western World; chemokine; cytokine; heart function; improved; in vivo; injured; mortality; mouse model; myocardial infarct sizing; neutrophil; novel strategies; prevent; tool

DESCRIPTION (provided by applicant): Myocardial infarction induced by ischemia/reperfusion (I/R) injury is a major clinical problem. During I/R injury, damage to the endothelial barrier allows a leakage of coagulation factors into the myocardium. Tissue factor (TF), the primary activator of the coagulation cascade, is constitutively expressed in the heart. Activation of coagulation cascade by TF has been shown to play a role in myocardial infarction after I/R injury. However, the role of TF:FVIIa signaling has not been investigated. The TF:FVIIa complex can activate cells by cleavage of protease activated receptor-2 (PAR-2). Both TF and PAR-2 are expressed on cardiomyocytes as well as neutrophils, which infiltrate into the myocardium after I/R injury. My preliminary data demonstrate that PAR-2 deficiency results in significant reduction of infarct size, heart remodeling and heart dysfunction after I/R injury. In this proposal I hypothesize that TF:FVIIa- dependent activation of PAR-2 on both neutrophils and cardiomyocytes contributes to myocardial infarction and heart remodeling. The proposal has two specific aims. In Specific Aim 1 I will investigate the role of TF:FVIIa-dependent activation of PAR-2 in infarct size using an in vivo mouse model of short-term I/R injury. In Specific Aim 2 I will determine how TF:FVIIa-PAR-2 pathway contributes to heart remodeling after long- term I/R injury. In my proposal I will use unique set of tools that allow me to distinguish between signaling and coagulation properties of TF:FVIIa complex. Understanding the role of TF:FVIIa-dependent activation of PAR-2 in injured heart may lead to the development of new therapies to reduce myocardial infarction and heart failure. PUBLIC HEALTH RELEVANCE: A heart attack, also called myocardial infarction, results in heart muscle damage and with time may lead to the heart failure. Reducing the size of the initial infarct decreases the chance of developing heart failure. Our data indicates that deficiency of protease activated receptor-2 (PAR-2) reduces initial infarct size, attenuates heart remodeling and improves heart function in mouse models of cardiac ischemia/reperfusion injury. Therefore, blocking PAR-2-dependent signaling may be a new strategy to prevent heart muscle damage after a heart attack and consequently reducing the chance of developing heart failure.

描述（由申请人提供）：缺血/再灌注（I/R）损伤引起的心肌梗塞是一个主要的临床问题。在I/R损伤期间，对内皮屏障的损害允许将凝血因子泄漏到心肌中。组织因子（TF）是凝血级联反应的主要激活因子，在心脏中构成表达。 TF激活凝血级联反应已显示在I/R损伤后在心肌梗塞中起作用。但是，尚未研究TF：FVIIA信号传导的作用。 TF：FVIIA复合物可以通过裂解蛋白酶活化受体-2（PAR-2）来激活细胞。 TF和PAR-2均在心肌细胞以及中性粒细胞上表达，它们在I/R损伤后浸润到心肌中。我的初步数据表明，PAR-2缺乏会导致I/R损伤后的梗塞大小，心脏重塑和心脏功能障碍的显着降低。在此提案中，我假设TF：FVIIA依赖于中性粒细胞和心肌细胞的PAR-2激活有助于心肌梗塞和心脏重塑。该提案有两个具体的目标。在特定目标1中，我将使用短期I/R损伤的体内小鼠模型来研究TF：FVIIA依赖性PAR-2在梗塞大小中的作用。在特定目标2中，我将确定TF：FVIIA-PAR-2途径在长期I/R损伤后如何促进心脏重塑。在我的提案中，我将使用一组独特的工具，使我可以区分TF：FVIIA复合物的信号传导和凝结属性。了解TF：FVIIA依赖性激活PAR-2在受伤的心脏中的作用可能导致发展新疗法以减少心肌梗塞和心力衰竭。 公共卫生相关性：心脏病发作，也称为心肌梗塞，会导致心肌损害，并且随着时间的流逝可能导致心力衰竭。减少初始梗塞的大小会减少发展心力衰竭的机会。我们的数据表明，蛋白酶活化受体-2（PAR-2）的缺乏会降低初始梗塞的大小，减轻心脏重塑并改善心脏缺血/再灌注损伤的小鼠模型中的心脏功能。因此，阻止PAR-2依赖性信号可能是一种新策略，可以防止心脏病发作后心肌损害，从而减少心力衰竭的机会。