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

描述(申请人提供)：由缺血/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入心肌。组织因子(TF)是凝血级联反应的主要激活剂，在心脏中有结构性表达。凝血因子激活凝血级联反应在I/R损伤后心肌梗死中起一定作用。然而，Tf：FVIIa信号转导途径的作用尚未被研究。Tf：FVIIa复合体可以通过裂解蛋白酶激活受体-2(PAR-2)来激活细胞。心肌细胞和中性粒细胞均表达TF和PAR-2，中性粒细胞在I/R损伤后进入心肌。我的初步数据显示，PAR-2缺乏可显著减少I/R损伤后的心肌梗死面积、心脏重塑和心功能障碍。在这项建议中，我假设中性粒细胞和心肌细胞上依赖于Tf：FVIIa的PAR-2激活有助于心肌梗死和心脏重塑。该提案有两个具体目标。在特定的目的1中，我将使用小鼠短期I/R损伤的在体模型来研究Tf：FVIIa依赖的PAR-2激活在脑梗塞范围中的作用。在特定的目标2中，我将确定TF：FVIIa-PAR-2通路在长期I/R损伤后心脏重构中的作用。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复合体的信号和凝血特性。了解Tf：FVIIa依赖的PAR-2激活在受损心脏中的作用可能有助于开发新的治疗方法来减少心肌梗死和心力衰竭。 公共卫生相关性：心脏病发作，也称为心肌梗死，会导致心肌损伤，随着时间的推移，可能会导致心力衰竭。缩小初始梗死面积可降低发生心力衰竭的几率。我们的数据表明，在小鼠心肌缺血/再灌注损伤模型中，蛋白水解酶激活受体-2(PAR-2)的缺失缩小了初始梗死范围，减轻了心脏重构，改善了心功能。因此，阻断PAR-2依赖的信号通路可能是预防心脏病发作后的心肌损伤从而降低发生心力衰竭的机会的一种新策略。

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.