학술논문
Therapeutic effects of angiotensin converting enzyme 2 (ACE2) enzyme activity on acute lung injury in COVID-19 / アンジオテンシン変換酵素2(ACE2)酵素活性によるCOVID-19急性肺傷害の治療効果
Document Type
Journal Article
Author
Daichi Utsumi; Haruhiko Kamada; Jianbo An; Keiji Kuba; Masamitsu Asaka; Mayumi Niiyama; Midori Hoshizaki; Satoru Nirasawa; Satoshi Nagata; Takafumi Minato; Tomokazu Yamaguchi; Wataru Kamitani; Yasuhiro Yasutomi; Yoshihiro Kawaoka; Yumiko Imai; 久場 敬司; 今井 由美子; 保富 康宏; 内海 大知; 安 健博; 山口 智和; 新山 真由美; 星崎 みどり; 永田 諭志; 河岡 義裕; 浅賀 正充; 湊 隆文; 神谷 亘; 鎌田 春彦; 韮澤 悟
Source
Proceedings for Annual Meeting of The Japanese Pharmacological Society. 2022, :2-041
Subject
Language
Japanese
ISSN
2435-4953
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 (Ang II) and thereby improves the pathologies of acute lung injury. To address whether the carboxypeptidase activity of ACE2 is protective in COVID-19, we investigated the effects of B38-CAP, an ACE2-like enzyme, on SARS-CoV-2-induced lung injury. Expression of endogenous ACE2 protein was significantly downregulated in the lungs of SARS-CoV-2-infected hamsters or human ACE2 transgenic mice, leading to elevation of Ang II levels. In vivo administration of recombinant SARS-CoV-2 Spike trimer also downregulated ACE2 expression, elevated Ang II levels and considerably worsened the symptoms of acute lung injury in hamsters exposed to acid aspiration. Despite its ACE2-like catalytic core, B38-CAP neither bound to Spike nor neutralized cell entry of SARS-CoV-2. However, treatment with B38-CAP improved the pathologies of Spike-augmented acid-induced lung injury. In SARS-CoV-2-infected hamsters, B38-CAP significantly improved lung edema and pathologies of lung injury without affecting viral RNA loads. Moreover, in human ACE2 transgenic mice, B38-CAP also attenuated SARS-CoV-2-induced lung edema and pathologies and improved lung functions. These results provide the first experimental in vivo evidence that increasing ACE2-like enzymatic activity is a potential therapeutic strategy to alleviate lung pathologies in COVID-19.