Department of Biochemistry and Metabolic Science, Akita University Graduate School of Medicine, Akita, Japan.
Laboratory of Regulation of Intractable Infectious Diseases, National Institute of Biomedical Innovation, Health and Nutrition (NIBIOHN), Ibaraki, Osaka, Japan.
PLoS One. 2022 Jul 22;17(7):e0270920. doi: 10.1371/journal.pone.0270920. eCollection 2022.
Angiotensin-converting enzyme 2 (ACE2) is the carboxypeptidase to degrade angiotensin II (Ang II) to angiotensin 1-7 (Ang 1-7) and improves the pathologies of cardiovascular disease and acute respiratory distress syndrome (ARDS)/acute lung injury. B38-CAP is a bacteria-derived ACE2-like carboxypeptidase as potent as human ACE2 and ameliorates hypertension, heart failure and SARS-CoV-2-induced lung injury in mice. Recombinant B38-CAP is prepared with E. coli protein expression system more efficiently than recombinant soluble human ACE2. Here we show therapeutic effects of B38-CAP on abdominal sepsis- or acid aspiration-induced acute lung injury. ACE2 expression was downregulated in the lungs of mice with cecal ligation puncture (CLP)-induced sepsis or acid-induced lung injury thereby leading to upregulation of Ang II levels. Intraperitoneal injection of B38-CAP significantly decreased Ang II levels while upregulated angiotensin 1-7 levels. B38-CAP improved survival rate of the mice under sepsis. B38-CAP suppressed the pathologies of lung inflammation, improved lung dysfunction and downregulated elevated cytokine mRNA levels in the mice with acute lung injury. Thus, systemic treatment with an ACE2-like enzyme might be a potential therapeutic strategy for the patients with severe sepsis or ARDS.
血管紧张素转换酶 2（ACE2）是一种羧肽酶，可将血管紧张素 II（Ang II）降解为血管紧张素 1-7（Ang 1-7），并改善心血管疾病和急性呼吸窘迫综合征（ARDS）/急性肺损伤的病理。B38-CAP 是一种细菌衍生的 ACE2 样羧肽酶，与人类 ACE2 一样有效，可改善高血压、心力衰竭和 SARS-CoV-2 诱导的小鼠肺损伤。与重组可溶性人 ACE2 相比，用大肠杆菌蛋白表达系统制备重组 B38-CAP 更有效。在这里，我们展示了 B38-CAP 对腹部脓毒症或酸吸入诱导的急性肺损伤的治疗作用。盲肠结扎穿刺（CLP）诱导的脓毒症或酸诱导的肺损伤小鼠肺中 ACE2 表达下调，导致 Ang II 水平上调。B38-CAP 腹腔注射可显著降低 Ang II 水平，同时上调血管紧张素 1-7 水平。B38-CAP 提高了脓毒症小鼠的存活率。B38-CAP 抑制了急性肺损伤小鼠肺部炎症的病理变化，改善了肺功能，并下调了升高的细胞因子 mRNA 水平。因此，全身性使用 ACE2 样酶可能是严重脓毒症或 ARDS 患者的一种潜在治疗策略。
