Faculty Collaboration Database

Protease-activated receptor 1 inhibition by SCH79797 attenuates left ventricular remodeling and profibrotic activities of cardiac fibroblasts. J Cardiovasc Pharmacol Ther 2013 Sep;18(5):460-75

Date

04/20/2013

Pubmed ID

23598708

Pubmed Central ID

PMC3771535

DOI

10.1177/1074248413485434

Scopus ID

2-s2.0-84882278338 (requires institutional sign-in at Scopus site)   57 Citations

Abstract

PURPOSE: Fibroblast activity promotes adverse left ventricular (LV) remodeling that underlies the development of ischemic cardiomyopathy. Transforming growth factor-β (TGF-β) is a potent stimulus for fibrosis, and the extracellular signal-regulated kinases(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 investigate the influence of a PAR1 inhibitor, SCH79797, on cardiac fibrosis, tissue stiffness and postinfarction remodeling, and effects of PAR1 inhibition on thrombin-induced TGF-β and (ERK) 1/2 activities in cardiac fibroblasts.

METHODS: We used a rat model of myocardial ischemia-reperfusion injury, isolated cardiac fibroblasts, and 3-dimensional (3D) cardiac tissue models fabricated to ascertain the contribution of PAR1 activation on cardiac fibrosis and LV remodeling.

RESULTS: The PAR1 inhibitor attenuated LV dilation and improved LV systolic function of the reperfused myocardium at 28 days. This improvement was associated with a nonsignificant 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 inhibition abolished thrombin-mediated ERK1/2 phosphorylation, TGF-β and type I procollagen production, matrix metalloproteinase-2/9 activation, 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 remodeling through late-stage antifibrotic events.

Author List

Sonin DL, Wakatsuki T, Routhu KV, Harmann LM, Petersen M, Meyer J, Strande JL

MESH terms used to index this publication - Major topics in bold

Animals
Disease Models, Animal
Fibroblasts
Fibrosis
Imaging, Three-Dimensional
Male
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
Myocardial Infarction
Myocardial Reperfusion Injury
Phosphorylation
Pyrroles
Quinazolines
Rats
Rats, Sprague-Dawley
Receptor, PAR-1
Transforming Growth Factor beta
Ventricular Remodeling