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

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.

• Authors: 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 Motoyama, Satoshi Nagata, Josef M Penninger, Haruhiko Kamada, Kwok-Yung Yuen, Wataru Kamitani, Ken Maeda, Yoshihiro Kawaoka, Yasuhiro Yasutomi, Yumiko Imai, Keiji Kuba
• Journal: Nature communications (Nat Commun) Vol. 12 Issue 1 Pg. 6791 (11 23 2021) ISSN: 2041-1723 [Electronic] England
• PMID: 34815389 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s).

Chemical References

• Spike Glycoprotein, Coronavirus
• spike protein, SARS-CoV-2
• Angiotensin II
• Carboxypeptidases
• ACE2 protein, human
• Angiotensin-Converting Enzyme 2

Topics

• Acute Lung Injury
• Angiotensin II
• Angiotensin-Converting Enzyme 2 (metabolism)
• Animals
• COVID-19 (pathology, prevention & control)
• Carboxypeptidases
• Chlorocebus aethiops
• Cricetinae
• Disease Models, Animal
• Female
• Humans
• Lung (pathology)
• Lung Injury (prevention & control)
• Male
• Mice
• Mice, Transgenic
• Pulmonary Edema (pathology, prevention & control)
• SARS-CoV-2 (drug effects)
• Spike Glycoprotein, Coronavirus (drug effects)
• Vero Cells
• Virus Internalization (drug effects)
• COVID-19 Drug Treatment