title: Protease-activated receptor 1 inhibition by SCH79797 attenuates left ventricular remodeling and profibrotic activities of cardiac fibroblasts.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  These studies suggest PAR1 inhibition initiated after ischemic injury attenuates adverse LV remodeling through late-stage antifibrotic events.
authors.affiliation: Division of Cardiovascular Medicine, Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Dmitry L
authors.initials: DL
authors.lastname: Sonin
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Wakatsuki
authors.forename: Kasi V
authors.initials: KV
authors.lastname: Routhu
authors.forename: Leanne M
authors.initials: LM
authors.lastname: Harmann
authors.forename: Matthew
authors.initials: M
authors.lastname: Petersen
authors.forename: Jennifer
authors.initials: J
authors.lastname: Meyer
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Strande
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D005355:Fibrosis; D021621:Imaging, Three-Dimensional; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009203:Myocardial Infarction / Q000188:drug therapy / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000503:physiopathology; D010766:Phosphorylation / Q000187:drug effects; D011758:Pyrroles / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016212:Transforming Growth Factor beta / Q000378:metabolism; D020257:Ventricular Remodeling / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors
chemical_list: C415424:N3-cyclopropyl-7-((4-(1-methylethyl)phenyl)methyl)-7H-pyrrolo(3, 2-f)quinazoline-1,3-diamine; D011758:Pyrroles; D011799:Quinazolines; D016212:Transforming Growth Factor beta; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D010975:Platelet Aggregation Inhibitors
keywords: 3D cell culture; cardiac fibrosis; ischemia–reperfusion; protease-activated receptor 1; remodeling; thrombin receptor antagonist