Abstract

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL071053-04
Application #
6925504
Study Section
Pathology A Study Section (PTHA)
Program Officer
Massicot-Fisher, Judith
Project Start
2002-08-01
Project End
2007-07-31
Budget Start
2005-08-01
Budget End
2007-07-31
Support Year
4
Fiscal Year
2005
Total Cost
$377,800
Indirect Cost

  Institution

Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037

  Publications

Bode, Michael F; Mackman, Nigel (2017) Erratum to ""A combined deficiency of tissue factor and PAR-4 is associated with fatal pulmonary hemorrhage in mice"" [Thromb. Res. 146 (2016) 46-50]. Thromb Res 149:95
Antoniak, Silvio; Sparkenbaugh, Erica M; Tencati, Michael et al. (2013) Protease activated receptor-2 contributes to heart failure. PLoS One 8:e81733
Pawlinski, Rafal; Tencati, Michael; Hampton, Craig R et al. (2007) Protease-activated receptor-1 contributes to cardiac remodeling and hypertrophy. Circulation 116:2298-306
Frank, Rolf Dario; Holscher, Todd; Schabbauer, Gernot et al. (2006) A non-anticoagulant synthetic pentasaccharide reduces inflammation in a murine model of kidney ischemia-reperfusion injury. Thromb Haemost 96:802-6