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Rivaroxaban attenuates cardiac hypertrophy by inhibiting protease-activated receptor-2 signaling in renin-overexpressing hypertensive mice

Hypertension Research volume 44, pages 1261–1273 (2021)Cite this article

Abstract

Rivaroxaban (Riv), a direct factor Xa (FXa) inhibitor, exerts anti-inflammatory effects in addition to anticoagulation. However, its role in cardiovascular remodeling is largely unknown. We tested the hypothesis that Riv attenuates the progression of cardiac hypertrophy and fibrosis induced by continuous activation of the renin–angiotensin system (RAS) in renin-overexpressing hypertensive transgenic (Ren-Tg) mice. We treated 12-week-old male Ren-Tg and wild-type (WT) mice with a diet containing Riv (12 mg/kg/day) or a regular diet for 4 weeks. After this, FXa in plasma significantly increased in Ren-Tg mice compared with WT mice, and Riv inhibited this increase. Left ventricular wall thickness (LVWT) and the area of cardiac fibrosis evaluated by Masson’s trichrome staining were greater in Ren-Tg mice than in WT mice, and Riv decreased them. Cardiac expression levels of the protease-activated receptor (PAR)-2, tumor necrosis factor-α, transforming growth factor (TGF)-β1, and collagen type 3 α1 (COL3A1) genes were all greater in Ren-Tg mice than in WT mice, and Riv attenuated these increases. To investigate the possible involvement of PAR-2, we treated Ren-Tg mice with a continuous subcutaneous infusion of 10 μg/kg/day of the PAR-2 antagonist FSLLRY for 4 weeks. FSLLRY significantly decreased LVWT and cardiac expression of PAR-2, TGF-β1, and COL3A1. In isolated cardiac fibroblasts (CFs), Riv or FSLLRY pretreatment inhibited the FXa-induced increase in the phosphorylation of extracellular signal-regulated kinases. In addition, Riv or FSLLRY inhibited FXa-stimulated wound closure in CFs. Riv exerts a protective effect against cardiac hypertrophy and fibrosis development induced by continuous activation of the RAS, partly by inhibiting PAR-2.

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Acknowledgements

We thank Nahomi Miyamoto, Ritsuko Kasai, and Chuya Murakami for their excellent technical support.

Funding

This work was partially supported by Bayer Yakuhin, Ltd., Japan.

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Authors and Affiliations

  1. Department of Cardiology and Nephrology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan

    Masato Narita, Kenji Hanada, Yosuke Kawamura, Hiroaki Ichikawa, Shuntaro Sakai, Yoshikazu Yokono, Maiko Senoo, Noritomo Narita, Michiko Shimada & Hirofumi Tomita

  2. Department of Health Promotion, Hirosaki University Graduate School of Health Sciences, Hirosaki, Japan

    Tomohiro Osanai

  3. Division of Cardiology, Saiseikai Kumamoto Hospital Cardiovascular Center, Kumamoto, Japan

    Ken Okumura

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  1. Masato Narita
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Correspondence to Hirofumi Tomita.

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HT received a scholarship or donation from Boehringer Ingelheim, Bayer, Daiichi-Sankyo, and Pfizer and speakers’ bureau/honorarium agreements from Boehringer Ingelheim, Bayer, and Daiichi-Sankyo. KO received speakers’ bureau/honorarium agreements from Daiichi-Sankyo, Boehringer Ingelheim, and Bayer. The remaining authors have no disclosures to report.

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Narita, M., Hanada, K., Kawamura, Y. et al. Rivaroxaban attenuates cardiac hypertrophy by inhibiting protease-activated receptor-2 signaling in renin-overexpressing hypertensive mice. Hypertens Res 44, 1261–1273 (2021). https://doi.org/10.1038/s41440-021-00700-7

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