Protease-Activated Receptor 1 Inhibition by SCH79797 Attenuates Left Ventricular Remodeling and Profibrotic Activities of Cardiac Fibroblasts

Sonin, Dmitry L.; Wakatsuki, Tetsuro; Routhu, Kasi V.; Harmann, Leanne M.; Petersen, Matthew; Meyer, Jennifer; Strande, Jennifer L.
September 2013
Journal of Cardiovascular Pharmacology & Therapeutics;Sep2013, Vol. 18 Issue 5, p460
Academic Journal
Purpose: Fibroblast activity promotes adverse left ventricular (LV) remodeling that underlies the development of ischemiccardiomyopathy. Transforming growth factor-β (TGF-β) is a potent stimulus for fibrosis, and the extracellular signal-regulatedkinases(ERK) 1/2 pathway also contributes to the fibrotic response. The thrombin receptor, protease-activated receptor 1(PAR1), has been shown to play an important role in the excessive fibrosis in different tissues. The aim of this study was to investigatethe influence of a PAR1 inhibitor, SCH79797, on cardiac fibrosis, tissue stiffness and postinfarction remodeling, and effectsof PAR1 inhibition on thrombin-induced TGF-β and (ERK) 1/2 activities in cardiac fibroblasts. Methods: We used a rat model ofmyocardial ischemia-reperfusion injury, isolated cardiac fibroblasts, and 3-dimensional (3D) cardiac tissue models fabricated toascertain the contribution of PAR1 activation on cardiac fibrosis and LV remodeling. Results: The PAR1 inhibitor attenuated LVdilation and improved LV systolic function of the reperfused myocardium at 28 days. This improvement was associated with anonsignificant decrease in scar size (%LV) from 23±% in the control group (n = 10) to 16%±5.5% in the treated group (n = 9;P = .052). In the short term, the PAR1 inhibitor did not rescue infarct size or LV systolic function after 3 days. The PAR1 inhibitionabolished thrombin-mediated ERK1/2 phosphorylation, TGF-β and type I procollagen production, matrix metalloproteinase-2/9activation, myofibroblasts transformation in vitro, and abrogated the remodeling of 3D tissues induced by chronic thrombin treatment.Conclusion: These studies suggest PAR1 inhibition initiated after ischemic injury attenuates adverse LV remodelingthrough late-stage antifibrotic events.


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