The complement C3-complement factor D-C3a receptor signalling axis regulates cardiac remodelling in right ventricular failure

Shogo Ito, Hisayuki Hashimoto, Hiroyuki Yamakawa, Dai Kusumoto, Yohei Akiba, Takahiro Nakamura, Mizuki Momoi, Jin Komuro, Toshiomi Katsuki, Mai Kimura, Yoshikazu Kishino, Shin Kashimura, Akira Kunitomi, Mark Lachmann, Masaya Shimojima, Gakuto Yozu, Chikaaki Motoda, Tomohisa Seki, Tsunehisa Yamamoto, Yoshiki ShinyaTakahiro Hiraide, Masaharu Kataoka, Takashi Kawakami, Kunimichi Suzuki, Kei Ito, Hirotaka Yada, Manabu Abe, Mizuko Osaka, Hiromi Tsuru, Masayuki Yoshida, Kenji Sakimura, Yoshihiro Fukumoto, Michisuke Yuzaki, Keiichi Fukuda, Shinsuke Yuasa

Research output: Contribution to journalArticlepeer-review

Abstract

Failure of the right ventricle plays a critical role in any type of heart failure. However, the mechanism remains unclear, and there is no specific therapy. Here, we show that the right ventricle predominantly expresses alternative complement pathway-related genes, including Cfd and C3aR1. Complement 3 (C3)-knockout attenuates right ventricular dysfunction and fibrosis in a mouse model of right ventricular failure. C3a is produced from C3 by the C3 convertase complex, which includes the essential component complement factor D (Cfd). Cfd-knockout mice also show attenuation of right ventricular failure. Moreover, the plasma concentration of CFD correlates with the severity of right ventricular failure in patients with chronic right ventricular failure. A C3a receptor (C3aR) antagonist dramatically improves right ventricular dysfunction in mice. In summary, we demonstrate the crucial role of the C3-Cfd-C3aR axis in right ventricular failure and highlight potential therapeutic targets for right ventricular failure.

Original languageEnglish
Article number5409
JournalNature communications
Volume13
Issue number1
DOIs
Publication statusPublished - 2022 Dec

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • General
  • Physics and Astronomy(all)

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