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

组织因子的作用：FVIIa-PAR-2 信号传导在心脏缺血/再灌注中的作用

• 批准号: 8207215
• 负责人: RAFAL L PAWLINSKI
• 金额: $ 36.28万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-15 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8207215
• 关键词: Attenuated; Blood Coagulation Factor; Cardiac; Cardiac Myocytes; Cells; Cicatrix; Clinical; Coagulation Process; Collagen; Complex; Data; Development; Extravasation; Factor VIIa; Fibrin split products; Fibrosis; Functional disorder; Generations; Goals; Growth; Heart; Heart failure; Infarction; Inflammation; Inflammatory; Lead; Modeling; Morbidity - disease rate; Myocardial Infarction; Myocardial Ischemia; Myocardial tissue; Myocardium; Outcome; Oxidative Stress; PAR-1 Receptor; PAR-2 Receptor; Pathologic; Pathway interactions; Play; Production; Property; Reactive Oxygen Species; Reperfusion Injury; Reperfusion Therapy; Role; Signal Transduction; Thrombin; Thromboplastin; Time; Tissues; Western World; chemokine; cytokine; heart function; improved; in vivo; injured; mortality; mouse model; myocardial infarct sizing; neutrophil; novel strategies; prevent; tool

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.

缺血/再灌注（I/R）损伤诱发的心肌梗死是临床上的一个主要疾病 问题。在 I/R 损伤期间，内皮屏障受损会导致 凝血因子进入心肌。组织因子（TF），主要激活剂 凝血级联在心脏中组成型表达。凝血激活 TF 级联已被证明在 I/R 损伤后的心肌梗塞中发挥作用。 然而，TF:FVIIa 信号传导的作用尚未得到研究。 TF:FVIIa 复合物可通过裂解蛋白酶激活受体 2 来激活细胞 （PAR-2）。 TF 和 PAR-2 均在心肌细胞和中性粒细胞上表达， I/R 损伤后渗入心肌。我的初步数据表明 PAR-2 缺乏会导致梗塞面积显着减小、心脏重塑 I/R 损伤后的心脏功能障碍。在这个提案中，我假设 TF:FVIIa- PAR-2 对中性粒细胞和心肌细胞的依赖性激活有助于 心肌梗塞和心脏重塑。该提案有两个具体目标。在 具体目标 1 我将研究 PAR-2 的 TF:FVIIa 依赖性激活在 使用短期 I/R 损伤的体内小鼠模型来测量梗塞大小。在具体目标 2 I 将确定 TF:FVIIa-PAR-2 通路如何促进长期心脏重塑 术语 I/R 损伤。 在我的提案中，我将使用一组独特的工具来区分 TF:FVIIa 复合物的信号传导和凝血特性。了解角色 受损心脏中 TF:FVIIa 依赖性的 PAR-2 激活可能导致心脏损伤的发生 减少心肌梗塞和心力衰竭的新疗法。