Blockade of PAR‐1 Signaling Attenuates Cardiac Hypertrophy and Fibrosis in Renin‐Overexpressing Hypertensive Mice. Issue 12 (16th June 2020)

• Record Type: Journal Article
• 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
• Is Part Of: Journal of the American Heart Association. Volume 9:Issue 12(2020)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-06-16
• Subjects: cardiac fibrosis -- cardiac hypertrophy -- factor Xa -- protease‐activated receptor -- renin–angiotensin system; Heart -- Diseases -- Periodicals; Cardiovascular system -- Diseases -- Periodicals; Cerebrovascular disease -- Periodicals; Cardiology -- Periodicals; 616.1
• DOI: 10.1161/JAHA.119.015616
• Languages: English
• ISSNs: 2047-9980

Abstract

Abstract : 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.