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: 8599478
• 负责人: RAFAL L PAWLINSKI
• 金额: $ 36.26万
• 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/8599478
• 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）损伤引起的心肌梗塞是主要的临床 问题。在I/R受伤期间，内皮屏障的损坏允许泄漏 凝血因子进入心肌。组织因子（TF），主要激活因子 凝血级联反应在心脏中组成型表达。凝血的激活 在I/R受伤后，TF的Cascade已显示出在心肌梗塞中发挥作用。 但是，尚未研究TF：FVIIA信号传导的作用。 TF：FVIIA复合物可以通过裂解蛋白酶活化受体-2激活细胞 （PAR-2）。 TF和PAR-2均在心肌细胞以及中性粒细胞上表达 I/R受伤后，它会浸润到心肌中。我的初步数据证明了 PAR-2缺乏导致梗塞大小显着降低，心脏重塑 I/R受伤后心脏功能障碍。在此提案中，我假设TF：fviia- PAR-2对中性粒细胞和心肌细胞的依赖激活有助于 心肌梗塞和心脏重塑。该提案有两个具体的目标。在 具体目的1我将研究TF：FVIIA依赖性PAR-2中的作用 使用短期I/R损伤的体内小鼠模型的梗塞大小。在特定的目标2 i 将确定TF：FVIIA-PAR-2途径在长期后有助于心脏重塑 学期I/R受伤。 在我的建议中，我将使用一套独特的工具，使我可以区分 TF：FVIIA复合物的信号传导和凝结特性。了解角色 TF：受伤心脏中PAR-2的FVIIA依赖性激活可能导致发展 减少心肌梗塞和心力衰竭的新疗法。