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

描述（由申请人提供）：缺血/再灌注（I/R）损伤引起的心肌梗死是一个主要的临床问题。在I/R损伤期间，内皮屏障的损伤允许凝血因子渗漏到心肌。组织因子（TF）是凝血级联的主要激活因子，在心脏中组成性表达。经证实，TF激活凝血级联在I/R损伤后心肌梗死中起作用。然而，TF:FVIIa信号的作用尚未被研究。TF:FVIIa复合体可以通过裂解蛋白酶激活受体2 （PAR-2）激活细胞。TF和PAR-2均在心肌细胞和中性粒细胞上表达，在I/R损伤后浸润到心肌中。我的初步数据表明，PAR-2缺乏导致I/R损伤后梗死面积、心脏重塑和心功能障碍显著减少。在这个提议中，我假设TF:FVIIa依赖性的PAR-2在中性粒细胞和心肌细胞上的激活有助于心肌梗死和心脏重塑。这项提议有两个具体目的。在Specific Aim 1中，我将使用短期I/R损伤小鼠体内模型研究TF: fviia依赖性PAR-2激活在梗死面积中的作用。在Specific Aim 2中，我将确定TF:FVIIa-PAR-2途径如何在长期I/R损伤后促进心脏重塑。在我的提案中，我将使用一套独特的工具，使我能够区分TF:FVIIa复合物的信号和凝固特性。了解TF: fviia依赖性的PAR-2在损伤心脏中的作用可能会导致新的治疗方法的发展，以减少心肌梗死和心力衰竭。

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.