TY - JOUR
T1 - The complement C3-complement factor D-C3a receptor signalling axis regulates cardiac remodelling in right ventricular failure
AU - Ito, Shogo
AU - Hashimoto, Hisayuki
AU - Yamakawa, Hiroyuki
AU - Kusumoto, Dai
AU - Akiba, Yohei
AU - Nakamura, Takahiro
AU - Momoi, Mizuki
AU - Komuro, Jin
AU - Katsuki, Toshiomi
AU - Kimura, Mai
AU - Kishino, Yoshikazu
AU - Kashimura, Shin
AU - Kunitomi, Akira
AU - Lachmann, Mark
AU - Shimojima, Masaya
AU - Yozu, Gakuto
AU - Motoda, Chikaaki
AU - Seki, Tomohisa
AU - Yamamoto, Tsunehisa
AU - Shinya, Yoshiki
AU - Hiraide, Takahiro
AU - Kataoka, Masaharu
AU - Kawakami, Takashi
AU - Suzuki, Kunimichi
AU - Ito, Kei
AU - Yada, Hirotaka
AU - Abe, Manabu
AU - Osaka, Mizuko
AU - Tsuru, Hiromi
AU - Yoshida, Masayuki
AU - Sakimura, Kenji
AU - Fukumoto, Yoshihiro
AU - Yuzaki, Michisuke
AU - Fukuda, Keiichi
AU - Yuasa, Shinsuke
N1 - Funding Information:
We thank all the members of our laboratory for their assistance. This research was supported by Grants-in-Aid for Scientific Research (JSPS KAKENHI, grant numbers 16H05304 (SY), 16K15415 (SY), 18K08047 (HY), 19H03622 (SY), 20H03678 (SY), 20K08461 (SY), 20K08193 (SY)), the SENSHIN Medical Research Foundation (SY), the Fukuda Foundation for Medical Technology (HY), the Daiwa Securities Health Foundation (HY), the Miyata Cardiac Research Promotion Foundation (HY), and Kawano Masanori Memorial Public Interest Incorporated Foundation for Promotion of Pediatrics (HY).
Funding Information:
K.F. is a founding scientist funded by the SAB of Heartseed Co., Ltd. All the other authors declare no competing interests.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-022-33152-9
DO - 10.1038/s41467-022-33152-9
M3 - Article
C2 - 36109509
AN - SCOPUS:85137919244
SN - 2041-1723
VL - 13
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 5409
ER -