학술논문
COVID-19マウスモデルにおけるACE2様カルボキシペプチダーゼB38-CAPによるSARS-CoV-2誘発性肺障害の抑制 / Suppression of SARS-CoV-2-induced lung injury by ACE2-like carboxypeptidase B38-CAP in COVID-19 mouse model
Document Type
Journal Article
Author
Daichi Utsumi; Haruhiko Kamada; Jianbo An; Keiji Kuba; Masaki Imai; Masamitsu Asaka; Mayumi Niiyama; Midori Hoshizaki; Saori Takahashi; Satoru Nirasawa; Satoshi Nagata; Takafumi Minato; Tomokazu Yamaguchi; Yasuhiro Yasutomi; Yoshihiro Kawaoka; Yumiko Imai; 久場 敬司; 今井 正樹; 今井 由美子; 保富 康弘; 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; 鎌田 春彦; 韮澤 悟; 高橋 砂織
Source
Proceedings for Annual Meeting of The Japanese Pharmacological Society. 2021, :2-LB48
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 the carboxypeptidase to degrade angiotensin II (Ang II) to angiotensin 1-7 and improves the pathologies of cardiovascular disease and acute lung injury. To address whether the carboxypeptidase enzymatic activity of ACE2 is protective against COVID-19, we investigated the effects of B38-CAP, an ACE2-like enzyme, on SARS-CoV-2-induced lung injury. Expression of ACE2 protein was significantly downregulated in the lungs of SARS-CoV-2-infected hamsters. Recombinant S1 domain or receptor-binding domain (RBD) of the SARS-CoV-2 Spike protein also directly downregulated ACE2 expression and elevated Ang II levels and considerably worsened acid-induced lung injury in hamsters. Treatment with B38-CAP downregulated Spike RBD-induced high Ang II levels, severe inflammation and pulmonary edema through its ACE2-like enzymatic activity. Consistently, elevated cytokine mRNA levels and impaired lung functions were improved by B38-CAP treatment. Moreover, in SARS-CoV-2-infected humanized ACE2 transgenic mice, B38-CAP significantly improved the pathologies of lung injury, alleviated the cytokine storms and downregulated viral RNA levels. These results provide the first experimental in vivo evidence that increasing ACE2-like enzymatic activity is a potential and powerful therapeutic strategy for lung pathologies in COVID-19.