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 - Funding Information:
We thank all members of our laboratories for technical assistance and helpful discussions. We thank Dr. Kiyoshi Tanabayashi at National Institute of Infectious Diseases for providing hACE2 Tg mice. K. K. is supported by the Kaken [20H03426, 20K21566] from Japanese Ministry of Science, the FY2020 Program to Develop Countermeasure Technologies against Viral and Other Infectious Diseases [24–136] from Japan Agency for Medical research and Development (AMED) and the Naito Foundation. Y.I. is supported by the Kaken [17H06179], T.Y. is supported by the Kaken [20K07285] from Japanese Ministry of Science and Takeda Science Foundation, J.A. is supported by the Kaken [20K16153] from Japanese Ministry of Science, and J.F.-W.C. is supported by Lo Ying Shek Chi Wai Foundation and the National Program on Key Research Project of China [2020YFA0707500 and 2020YFA0707504]. J.M.P. received funding from the T. von Zastrow foundation, the FWF Wittgenstein award (Z 271-B19), the Austrian Academy of Sciences, the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No 101005026, and the Canada 150 Research Chairs Program F18–01336 as well as the Canadian Institutes of Health Research COVID-19 grants F20–02343 and F20–02015.
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.
UR - http://www.scopus.com/inward/record.url?scp=85119866320&partnerID=8YFLogxK
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 -
