TY - JOUR
T1 - ACE2-like carboxypeptidase B38-CAP protects from SARS-CoV-2-induced lung injury
AU - Yamaguchi, Tomokazu
AU - Hoshizaki, Midori
AU - Minato, Takafumi
AU - Nirasawa, Satoru
AU - Asaka, Masamitsu N.
AU - Niiyama, Mayumi
AU - Imai, Masaki
AU - Uda, Akihiko
AU - Chan, Jasper Fuk Woo
AU - Takahashi, Saori
AU - An, Jianbo
AU - Saku, Akari
AU - Nukiwa, Ryota
AU - Utsumi, Daichi
AU - Kiso, Maki
AU - Yasuhara, Atsuhiro
AU - Poon, Vincent Kwok Man
AU - Chan, Chris Chung Sing
AU - Fujino, Yuji
AU - Motoyama, Satoru
AU - Nagata, Satoshi
AU - Penninger, Josef M.
AU - Kamada, Haruhiko
AU - Yuen, Kwok Yung
AU - Kamitani, Wataru
AU - Maeda, Ken
AU - Kawaoka, Yoshihiro
AU - Yasutomi, Yasuhiro
AU - Imai, Yumiko
AU - Kuba, Keiji
N1 - Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85119866320&partnerID=8YFLogxK
U2 - 10.1038/s41467-021-27097-8
DO - 10.1038/s41467-021-27097-8
M3 - Article
C2 - 34815389
AN - SCOPUS:85119866320
SN - 2041-1723
VL - 12
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 6791
ER -