Blockade of PAR-1 Signaling Attenuates Cardiac Hypertrophy and Fibrosis in Renin-Overexpressing Hypertensive Mice

• Published in: Journal of the American Heart Association 2020-06, Vol.9 (12), p.e015616
• Main Authors: Yokono, Yoshikazu, Hanada, Kenji, Narita, Masato, Tatara, Yota, Kawamura, Yousuke, Miura, Naotake, Kitayama, Kazutaka, Nakata, Masamichi, Nozaka, Masashi, Kato, Tomo, Kudo, Natsumi, Tsushima, Michiko, Toyama, Yuichi, Itoh, Ken, Tomita, Hirofumi
• Format: Article
• Language: English
• Subjects: Animals; cardiac fibrosis; cardiac hypertrophy; Collagen Type III - genetics; Collagen Type III - metabolism; Cytokines - metabolism; Disease Models, Animal; Extracellular Signal-Regulated MAP Kinases - metabolism; factor Xa; Fibroblasts - drug effects; Fibroblasts - metabolism; Fibrosis; HEK293 Cells; Humans; Hypertension - drug therapy; Hypertension - genetics; Hypertension - metabolism; Hypertension - physiopathology; Hypertrophy, Left Ventricular - genetics; Hypertrophy, Left Ventricular - metabolism; Hypertrophy, Left Ventricular - physiopathology; Hypertrophy, Left Ventricular - prevention & control; Inflammation Mediators - metabolism; Macrophages - drug effects; Macrophages - metabolism; Male; Mice, Inbred C57BL; Mice, Transgenic; Myocardium - metabolism; Myocardium - pathology; Original Research; protease‐activated receptor; Pyrroles - pharmacology; Quinazolines - pharmacology; Receptor, PAR-1 - antagonists & inhibitors; Receptor, PAR-1 - genetics; Receptor, PAR-1 - metabolism; Renin - genetics; Renin - metabolism; renin–angiotensin system; Signal Transduction; Transforming Growth Factor beta1 - genetics; Transforming Growth Factor beta1 - metabolism; Up-Regulation; Ventricular Function, Left - drug effects; Ventricular Remodeling - drug effects
• ISSN: 2047-9980; 2047-9980
• DOI: 10.1161/JAHA.119.015616

Background Although PAR-1 (protease-activated receptor-1) exerts important functions in the pathophysiology of the cardiovascular system, the role of PAR-1 signaling in heart failure development remains largely unknown. We tested the hypothesis that PAR-1 signaling inhibition has protective effects on the progression of cardiac remodeling induced by chronic renin-angiotensin system activation using renin-overexpressing hypertensive (Ren-Tg) mice. Methods and Results We treated 12- to 16-week-old male wild-type (WT) mice and Ren-Tg mice with continuous subcutaneous infusion of the PAR-1 antagonist SCH79797 or vehicle for 4 weeks. The thicknesses of interventricular septum and the left ventricular posterior wall were greater in Ren-Tg mice than in WT mice, and SCH79797 treatment significantly decreased these thicknesses in Ren-Tg mice. The cardiac fibrosis area and monocyte/macrophage deposition were greater in Ren-Tg mice than in WT mice, and both conditions were attenuated by SCH79797 treatment. Cardiac mRNA expression levels of PAR-1, TNF-α (tumor necrosis factor-α), TGF-β1 (transforming growth factor-β1), and COL3A1 (collagen type 3 α1 chain) and the ratio of β-myosin heavy chain (β-MHC) to α-MHC were all greater in Ren-Tg mice than in WT mice; SCH79797 treatment attenuated these increases in Ren-Tg mice. Prothrombin fragment 1+2 concentration and factor Xa in plasma were greater in Ren-Tg mice than in WT mice, and both conditions were unaffected by SCH79797 treatment. In isolated cardiac fibroblasts, both thrombin and factor Xa enhanced ERK1/2 (extracellular signal-regulated kinase 1/2) phosphorylation, and SCH79797 pretreatment abolished this enhancement. Furthermore, gene expression of PAR-1, TGF-β1, and COL3A1 were enhanced by factor Xa, and all were inhibited by SCH79797. Conclusions The results indicate that PAR-1 signaling is involved in cardiac remodeling induced by renin-angiotensin system activation, which may provide a novel therapeutic target for heart failure.