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: 8039581
• 负责人: RAFAL L PAWLINSKI
• 金额: $ 36.42万
• 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/8039581
• 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

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.

描述（由申请人提供）：缺血/再灌注（I/R）损伤引起的心肌梗塞是一个主要的临床问题。在 I/R 损伤期间，内皮屏障受损导致凝血因子渗漏到心肌中。组织因子（TF）是凝血级联的主要激活剂，在心脏中持续表达。 TF 激活的凝血级联已被证明在 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 (PAR-2) 来激活细胞。 TF 和 PAR-2 均在心肌细胞和中性粒细胞上表达，I/R 损伤后中性粒细胞会渗入心肌。我的初步数据表明，PAR-2 缺乏会导致 I/R 损伤后梗塞面积、心脏重塑和心功能障碍显着减少。在这个提议中，我假设中性粒细胞和心肌细胞上 TF:FVIIa 依赖性的 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。在具体目标 1 中，我将使用短期 I/R 损伤的体内小鼠模型研究 PAR-2 的 TF:FVIIa 依赖性激活在梗塞面积中的作用。在具体目标 2 中，我将确定 TF:FVIIa-PAR-2 通路如何促进长期 I/R 损伤后的心脏重塑。在我的提案中，我将使用一套独特的工具来区分 TF:FVIIa 复合物的信号传导和凝血特性。了解 TF:FVIIa 依赖性 PAR-2 激活在受损心脏中的作用可能有助于开发新疗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，也称为心肌梗塞，会导致心肌损伤，随着时间的推移可能会导致心力衰竭。减少最初梗塞的范围可以降低发生心力衰竭的机会。我们的数据表明，在心脏缺血/再灌注损伤的小鼠模型中，蛋白酶激活受体-2 (PAR-2) 的缺乏会减少初始梗塞面积，减弱心脏重塑并改善心脏功能。因此，阻断 PAR-2 依赖性信号传导可能是预防心脏病发作后心肌损伤的新策略，从而减少发生心力衰竭的机会。