title: Protease activated receptor-2 contributes to heart failure.
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.
authors: UNC McAllister Heart Institute, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors: Silvio
authors: S
authors: Antoniak
authors: Erica M
authors: EM
authors: Sparkenbaugh
authors: Michael
authors: M
authors: Tencati
authors: Mauricio
authors: M
authors: Rojas
authors: Nigel
authors: N
authors: Mackman
authors: Rafal
authors: R
authors: Pawlinski
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D003331:Coronary Vessels / Q000601:surgery; D005355:Fibrosis; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006333:Heart Failure / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D006984:Hypertrophy / Q000378:metabolism; D008026:Ligation / Q000009:adverse effects; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors; D009203:Myocardial Infarction / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011480:Protease Inhibitors / Q000494:pharmacology; D044464:Receptor, PAR-2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D024723:Ventricular Myosins / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
chemical_list: D011480:Protease Inhibitors; D044464:Receptor, PAR-2; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D024723:Ventricular Myosins