Thrombin-PAR-1 Signaling in Cardiac I/R Injury

Scripps Research Institute, La Jolla CA

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Abstract

DESCRIPTION (provided by applicant): Myocardial I/R injury is a significant clinical problem and contributes to loss of myocardial tissue after restoration of blood flow after angioplasty, after administration of thrombolytics and following coronary artery bypass surgery. The broad, long-term goal of this proposal is to understand how thrombin contributes to inflammation during myocardial ischemia-reperfusion (I/R) injury. Our preliminary data suggest that I/R injury induces endothelial cell damage and leakage of clotting factors into the myocardium. Cardiomyocyte tissue factor initiates the clotting cascade and generates the coagulation protease thrombin. We hypothesize that thrombin cleavage of PAR-1 on endothelial cells increases the expression of proinflammatory mediators, such as KC and MCP-1, and recruitment of PMNs. The proposal contains three specific aims. Specific Aim 1 will determine the role of PAR-1 in myocardial I/R injury. Specific Aim 2 will determine the expression pattern of Egr-l and its role in myocardial L/R injury. Specific Aim 3 will identify thrombin-PAR-1-dependent inflammatory genes in myocardial I/R injury. Our studies should increase the fundamental knowledge of the role of the thrombin-PAR-1 signaling pathway in myocardial I/R injury and may lead to the development of novel therapies to preserve ischemic myocardium.