Protease Activated Receptor-2 Contributes to Heart Failure |
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| Authors: | Silvio Antoniak Erica M Sparkenbaugh Michael Tencati Mauricio Rojas Nigel Mackman Rafal Pawlinski |
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| Institution: | 1. UNC McAllister Heart Institute, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.; 2. Department of Microbiology, University of Illinois at Urbana-Champaign, Urbana-Champaign, Illinois, United States of America.; University of Western Ontario, Canada, |
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| Abstract: | Heart failure is a major clinical problem worldwide. Previous studies have demonstrated an important role for G protein-coupled receptors, including protease-activated receptors (PARs), in the pathology of heart hypertrophy and failure. Activation of PAR-2 on cardiomyocytes has been shown to induce hypertrophic growth in vitro. PAR-2 also contributes to myocardial infarction and heart remodeling after ischemia/reperfusion injury. In this study, we found that PAR-2 induced hypertrophic growth of cultured rat neonatal cardiomyocytes in a MEK1/2 and p38 dependent manner. In addition, PAR-2 activation on mouse cardiomyocytes increased expression of the pro-fibrotic chemokine MCP-1. Furthermore, cardiomyocyte-specific overexpression of PAR-2 in mice induced heart hypertrophy, cardiac fibrosis, inflammation and heart failure. Finally, in a mouse model of myocardial infarction induced by permanent ligation of the left anterior descending coronary artery, PAR-2 deficiency attenuated heart remodeling and improved heart function independently of its contribution to the size of the initial infarct. Taken together, our data indicate that PAR-2 signaling contributes to the pathogenesis of hypertrophy and heart failure. |
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