Blockade of PAR‐1 Signaling Attenuates Cardiac Hypertrophy and Fibrosis in Renin‐Overexpressing Hypertensive Mice
| Autor: | Yousuke Kawamura, Kazutaka Kitayama, Michiko Tsushima, Masashi Nozaka, Tomo Kato, Yoshikazu Yokono, Masamichi Nakata, Natsumi Kudo, Yota Tatara, Kenji Hanada, Naotake Miura, Yuichi Toyama, Masato Narita, Hirofumi Tomita, Ken Itoh |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Male
Cardiac fibrosis factor Xa cardiac fibrosis 030204 cardiovascular system & hematology Ventricular Function Left 0302 clinical medicine Fibrosis Renin Protease-activated receptor Extracellular Signal-Regulated MAP Kinases renin–angiotensin system Original Research 0303 health sciences Ventricular Remodeling cardiac hypertrophy Pathophysiology Up-Regulation Cardiac hypertrophy Hypertension Cytokines Hypertrophy Left Ventricular Inflammation Mediators Cardiology and Cardiovascular Medicine Signal Transduction medicine.medical_specialty Mice Transgenic ACE/Angiotension Receptors/Renin Angiotensin System Transforming Growth Factor beta1 03 medical and health sciences Internal medicine Renin–angiotensin system medicine Animals Humans Pyrroles Receptor PAR-1 030304 developmental biology Heart Failure business.industry Macrophages Myocardium Hypertrophy Fibroblasts medicine.disease Blockade Mice Inbred C57BL Disease Models Animal Endocrinology Collagen Type III HEK293 Cells Heart failure Quinazolines protease‐activated receptor business |
| Zdroj: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| ISSN: | 2047-9980 |
| Popis: | 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 SCH 79797 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 SCH 79797 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 SCH 79797 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; SCH 79797 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 SCH 79797 treatment. In isolated cardiac fibroblasts, both thrombin and factor Xa enhanced ERK1/2 (extracellular signal‐regulated kinase 1/2) phosphorylation, and SCH 79797 pretreatment abolished this enhancement. Furthermore, gene expression of PAR ‐1, TGF ‐β1, and COL 3A1 were enhanced by factor Xa, and all were inhibited by SCH 79797. 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. |
| Databáze: | OpenAIRE |
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