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

由缺血/再灌注(I/R)损伤引起的心肌梗死是一种主要的临床疾病 有问题。在I/R损伤期间，内皮屏障的损伤导致血管内皮细胞的渗漏 凝血因子进入心肌。组织因子(Tf)是血管紧张素转换酶的主要激活剂 凝血级联，在心脏中有结构性的表达。激活凝血 血管紧张素转运蛋白的级联反应在I/R损伤后心肌梗死中起一定作用。 然而，Tf：FVIIa信号转导的作用尚未被研究。 Tf：FVIIa复合体可通过裂解蛋白酶激活的受体-2激活细胞 (标准杆-2)。Tf和PAR-2在心肌细胞和中性粒细胞上均有表达， 在I/R损伤后，它们渗入到心肌中。我的初步数据显示 PAR-2缺乏可显著缩小心肌梗死面积、心脏重塑 和I/R损伤后心功能不全。在这项提议中，我假设Tf：FVIIa- 中性粒细胞和心肌细胞上PAR-2的依赖激活有助于 心肌梗死和心脏重塑。该提案有两个具体目标。在……里面 具体目的1我将研究Tf：FVIIa依赖的PAR-2激活在血管内皮细胞中的作用 采用在体小鼠短期I/R损伤模型研究脑梗塞范围。在具体目标2中 将确定Tf：FVIIa-PAR-2通路在长时间心脏重构中的作用 期性I/R损伤。 在我的提案中，我将使用一套独特的工具来区分 Tf：FVIIa复合体的信号和凝血特性。了解企业的角色 Tf：FVIIa依赖的PAR-2在损伤心脏中的激活可能导致 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.