Protease-activated receptor 1 inhibition by SCH79797 attenuates left ventricular remodeling and profibrotic activities of cardiac fibroblasts.

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.

• Authors: Dmitry L Sonin, Tetsuro Wakatsuki, Kasi V Routhu, Leanne M Harmann, Matthew Petersen, Jennifer Meyer, Jennifer L Strande
• Journal: Journal of cardiovascular pharmacology and therapeutics (J Cardiovasc Pharmacol Ther) Vol. 18 Issue 5 Pg. 460-75 (Sep 2013) ISSN: 1940-4034 [Electronic] United States
• PMID: 23598708 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• N3-cyclopropyl-7-((4-(1-methylethyl)phenyl)methyl)-7H-pyrrolo(3, 2-f)quinazoline-1,3-diamine
• Pyrroles
• Quinazolines
• Receptor, PAR-1
• Transforming Growth Factor beta
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3

Topics

• Animals
• Disease Models, Animal
• Fibroblasts (drug effects, metabolism)
• Fibrosis
• Imaging, Three-Dimensional
• Male
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3 (metabolism)
• Myocardial Infarction (drug therapy, physiopathology)
• Myocardial Reperfusion Injury (drug therapy, physiopathology)
• Phosphorylation (drug effects)
• Pyrroles (pharmacology)
• Quinazolines (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Receptor, PAR-1 (antagonists & inhibitors)
• Transforming Growth Factor beta (metabolism)
• Ventricular Remodeling (drug effects)