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

缺血/再灌注（I/R）损伤引起的心肌梗死是临床上的主要疾病 问题.在I/R损伤过程中，内皮屏障的损伤允许血管内皮细胞的渗漏。 凝血因子进入心肌。组织因子（TF），主要的激活剂， 凝血级联反应在心脏中组成性表达。激活凝血 TF的级联反应在I/R损伤后的心肌梗死中起作用。 然而，TF：FVIIa信号传导的作用尚未得到研究。 TF：FVIIa复合物可通过切割蛋白酶激活的受体-2来激活细胞 （PAR-2）。TF和PAR-2都在心肌细胞以及中性粒细胞上表达， I/R损伤后，其浸润到心肌中。我的初步数据显示 PAR-2缺乏导致梗死面积显著减小，心脏重塑 I/R损伤后的心脏功能障碍。在这个建议中，我假设TF：FVIIa- PAR-2在中性粒细胞和心肌细胞上的依赖性激活有助于 心肌梗死和心脏重塑。该提案有两个具体目标。在 具体目的1我将研究TF：FVIIa依赖性PAR-2激活在 使用短期I/R损伤的体内小鼠模型测量梗死面积。特别目标2 将确定TF：FVIIa-PAR-2通路如何促进长期心脏重塑， 长期I/R损伤 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性质。理解的作用 TF：损伤心脏中PAR-2的FVIIa依赖性激活可能导致 减少心肌梗死和心力衰竭的新疗法。

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 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.