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(Circulation. 2007;116:2298-2306.)
© 2007 American Heart Association, Inc.

Molecular Cardiology

Protease-Activated Receptor-1 Contributes to Cardiac Remodeling and Hypertrophy

Rafal Pawlinski, PhD; Michael Tencati, BS; Craig R. Hampton, MD; Tetsuro Shishido, MD, PhD; Tara A. Bullard, PhD; Liam M. Casey, MD; Patricia Andrade-Gordon, PhD; Matthias Kotzsch, MD; Denise Spring, PhD; Thomas Luther, MD; Jun-ichi Abe, MD, PhD; Timothy H. Pohlman, MD; Edward D. Verrier, MD; Burns C. Blaxall, PhD; Nigel Mackman, PhD

From The Scripps Research Institute (R.P., M.T., N.M.), Department of Immunology, La Jolla, Calif; University of Washington (C.R.H., D.S., T.H.P., E.D.V.), Division of Cardiothoracic Surgery, Seattle, Wash; University of Rochester Medical Center (T.S., T.A.B., L.M.C., J.A., B.C.B.), Cardiovascular Research Institute, Rochester, New York; Johnson & Johnson Pharmaceutical Research and Development, LLC (P.A.-G.), Spring House, Pa; and Institute of Pathology (M.K., T.L.), Technical University of Dresden, Dresden, Germany.

Correspondence to Nigel Mackman, PhD, The Scripps Research Institute, Department of Immunology, SP30-3040, 10550 N Torrey Pines Rd, La Jolla, CA 92037. E-mail nmackman{at}scripps.edu

Received January 25, 2007; accepted September 14, 2007.

Background— Protease-activated receptor-1 (PAR-1) is the high-affinity receptor for the coagulation protease thrombin. It is expressed by a variety of cell types in the heart, including cardiomyocytes and cardiac fibroblasts. We have shown that tissue factor (TF) and thrombin contribute to infarct size after cardiac ischemia-reperfusion (I/R) injury. Moreover, in vitro studies have shown that PAR-1 signaling induces hypertrophy of cardiomyocytes and proliferation of cardiac fibroblasts. The purpose of the present study was to investigate the role of PAR-1 in infarction, cardiac remodeling, and hypertrophy after I/R injury. In addition, we analyzed the effect of overexpression of PAR-1 on cardiomyocytes.

Methods and Results— We found that PAR-1 deficiency reduced dilation of the left ventricle and reduced impairment of left ventricular function 2 weeks after I/R injury. Activation of ERK1/2 was increased in injured PAR-1^–/– mice compared with wild-type mice; however, PAR-1 deficiency did not affect infarct size. Cardiomyocyte-specific overexpression of PAR-1 in mice induced eccentric hypertrophy (increased left ventricular dimension and normal left ventricular wall thickness) and dilated cardiomyopathy. Deletion of the TF gene in cardiomyocytes reduced the eccentric hypertrophy in mice overexpressing PAR-1.

Conclusions— Our results demonstrate that PAR-1 contributes to cardiac remodeling and hypertrophy. Moreover, overexpression of PAR-1 on cardiomyocytes induced eccentric hypertrophy. Inhibition of PAR-1 after myocardial infarction may represent a novel therapy to reduce hypertrophy and heart failure in humans.

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				J. L. Strande Letter by Strande Regarding Article "Protease-Activated Receptor-1 Contributes to Cardiac Remodeling and Hypertrophy" Circulation, June 17, 2008; 117(24): e495 - e495. [Full Text] [PDF]

				R. Pawlinski, M. Tencati, C. R. Hampton, D. Spring, T. H. Pohlman, E. D. Verrier, T. Shishido, T. A. Bullard, L. M. Casey, J.-i. Abe, et al. Response to Letter Regarding Article, "Protease-Activated Receptor-1 Contributes to Cardiac Remodeling and Hypertrophy" Circulation, June 17, 2008; 117(24): e496 - e496. [Full Text] [PDF]