ACE2-like carboxypeptidase B38-CAP protects from SARS-CoV-2-induced lung injury

Tomokazu Yamaguchi, Midori Hoshizaki, Takafumi Minato, Satoru Nirasawa, Masamitsu N. Asaka, Mayumi Niiyama, Masaki Imai, Akihiko Uda, Jasper Fuk Woo Chan, Saori Takahashi, Jianbo An, Akari Saku, Ryota Nukiwa, Daichi Utsumi, Maki Kiso, Atsuhiro Yasuhara, Vincent Kwok Man Poon, Chris Chung Sing Chan, Yuji Fujino, Satoru MotoyamaSatoshi Nagata, Josef M. Penninger, Haruhiko Kamada, Kwok Yung Yuen, Wataru Kamitani, Ken Maeda, Yoshihiro Kawaoka, Yasuhiro Yasutomi, Yumiko Imai, Keiji Kuba

Research output: Contribution to journalArticlepeer-review

29 Citations (Scopus)

Abstract

Angiotensin-converting enzyme 2 (ACE2) is a receptor for cell entry of SARS-CoV-2, and recombinant soluble ACE2 protein inhibits SARS-CoV-2 infection as a decoy. ACE2 is a carboxypeptidase that degrades angiotensin II, thereby improving the pathologies of cardiovascular disease or acute lung injury. Here we show that B38-CAP, an ACE2-like enzyme, is protective against SARS-CoV-2-induced lung injury. Endogenous ACE2 expression is downregulated in the lungs of SARS-CoV-2-infected hamsters, leading to elevation of angiotensin II levels. Recombinant Spike also downregulates ACE2 expression and worsens the symptoms of acid-induced lung injury. B38-CAP does not neutralize cell entry of SARS-CoV-2. However, B38-CAP treatment improves the pathologies of Spike-augmented acid-induced lung injury. In SARS-CoV-2-infected hamsters or human ACE2 transgenic mice, B38-CAP significantly improves lung edema and pathologies of lung injury. These results provide the first in vivo evidence that increasing ACE2-like enzymatic activity is a potential therapeutic strategy to alleviate lung pathologies in COVID-19 patients.

Original languageEnglish
Article number6791
JournalNature communications
Volume12
Issue number1
DOIs
Publication statusPublished - Dec 2021
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General Chemistry
  • General Biochemistry,Genetics and Molecular Biology
  • General Physics and Astronomy

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