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，对内皮屏障的损伤允许凝血因子渗漏到心肌中。组织因子（TF）是凝血级联反应的主要激活剂，在心脏中组成型表达。TF激活凝血级联反应在I/R损伤后的心肌梗死中发挥作用。然而，TF：FVIIa信号传导的作用尚未被研究。TF：FVIIa复合物可通过切割蛋白酶激活受体-2（PAR-2）来激活细胞。TF和PAR-2在心肌细胞以及中性粒细胞上表达，I/R损伤后中性粒细胞浸润到心肌中。我的初步数据表明，PAR-2缺乏导致I/R损伤后梗死面积显著减少，心脏重塑和心功能障碍。在这个提议中，我假设中性粒细胞和心肌细胞上PAR-2的TF：FVIIa依赖性激活有助于心肌梗死和心脏重塑。该提案有两个具体目标。在具体目标1中，我将使用短期I/R损伤的体内小鼠模型研究PAR-2的TF：FVIIa依赖性激活在梗死面积中的作用。在具体目标2中，我将确定TF：FVIIa-PAR-2通路如何在长期I/R损伤后促进心脏重塑。在我的建议中，我将使用一套独特的工具，使我能够区分TF：FVIIa复合物的信号传导和凝血特性。了解TF：FVIIa依赖性激活PAR-2在受损心脏中的作用可能会导致新疗法的开发，以减少心肌梗死和心力衰竭。 公共卫生相关性：心脏病发作，也称为心肌梗塞，会导致心肌损伤，随着时间的推移可能会导致心力衰竭。缩小初始梗死的面积可以降低发生心力衰竭的机会。我们的数据表明，蛋白酶激活受体-2（PAR-2）的缺陷减少初始梗死面积，减弱心脏重构和改善心脏缺血/再灌注损伤小鼠模型的心功能。因此，阻断PAR-2依赖性信号传导可能是预防心脏病发作后心肌损伤的新策略，从而减少发生心力衰竭的机会。

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.