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 Shinya, Takahiro 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 and Shinsuke Yuasa ()
Additional contact information
Shogo Ito: Keio University School of Medicine
Hisayuki Hashimoto: Keio University School of Medicine
Hiroyuki Yamakawa: Keio University School of Medicine
Dai Kusumoto: Keio University School of Medicine
Yohei Akiba: Keio University School of Medicine
Takahiro Nakamura: Keio University School of Medicine
Mizuki Momoi: Keio University School of Medicine
Jin Komuro: Keio University School of Medicine
Toshiomi Katsuki: Keio University School of Medicine
Mai Kimura: Keio University School of Medicine
Yoshikazu Kishino: Keio University School of Medicine
Shin Kashimura: Keio University School of Medicine
Akira Kunitomi: Keio University School of Medicine
Mark Lachmann: Keio University School of Medicine
Masaya Shimojima: Keio University School of Medicine
Gakuto Yozu: Keio University School of Medicine
Chikaaki Motoda: Keio University School of Medicine
Tomohisa Seki: Keio University School of Medicine
Tsunehisa Yamamoto: Keio University School of Medicine
Yoshiki Shinya: Keio University School of Medicine
Takahiro Hiraide: Keio University School of Medicine
Masaharu Kataoka: Keio University School of Medicine
Takashi Kawakami: Keio University School of Medicine
Kunimichi Suzuki: Keio University School of Medicine
Kei Ito: National Defense Medical College
Hirotaka Yada: National Defense Medical College
Manabu Abe: Brain Research Institute, Niigata University
Mizuko Osaka: Tokyo Medical and Dental University
Hiromi Tsuru: Tokyo Medical and Dental University
Masayuki Yoshida: Tokyo Medical and Dental University
Kenji Sakimura: Brain Research Institute, Niigata University
Yoshihiro Fukumoto: Kurume University School of Medicine
Michisuke Yuzaki: Keio University School of Medicine
Keiichi Fukuda: Keio University School of Medicine
Shinsuke Yuasa: Keio University School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-33152-9

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