B38-CAP is a bacteria-derived ACE2-like enzyme that suppresses hypertension and cardiac dysfunction

Minato, Takafumi; Nirasawa, Satoru; Sato, Teruki; Yamaguchi, Tomokazu; Hoshizaki, Midori; Inagaki, Tadakatsu; Nakahara, Kazuhiko; Yoshihashi, Tadashi; Ozawa, Ryo; Yokota, Saki; Natsui, Miyuki; Koyota, Souichi; Yoshiya, Taku; Yoshizawa-Kumagaye, Kumiko; Motoyama, Satoru; Gotoh, Takeshi; Nakaoka, Yoshikazu; Penninger, Josef M.; Watanabe, Hiroyuki; Imai, Yumiko; Takahashi, Saori; Kuba, Keiji

Angiotensin-converting enzyme 2 (ACE2) is critically involved in cardiovascular physiology and pathology, and is currently clinically evaluated to treat acute lung failure. Here we show that the B38-CAP, a carboxypeptidase derived from Paenibacillus sp. B38, is an ACE2-like enzyme to decrease angiotensin II levels in mice. In protein 3D structure analysis, B38-CAP homolog shares structural similarity to mammalian ACE2 with low sequence identity. In vitro, recombinant B38-CAP protein catalyzed the conversion of angiotensin II to angiotensin 1–7, as well as other known ACE2 target peptides. Treatment with B38-CAP suppressed angiotensin II-induced hypertension, cardiac hypertrophy, and fibrosis in mice. Moreover, B38-CAP inhibited pressure overload-induced pathological hypertrophy, myocardial fibrosis, and cardiac dysfunction in mice. Our data identify the bacterial B38-CAP as an ACE2-like carboxypeptidase, indicating that evolution has shaped a bacterial carboxypeptidase to a human ACE2-like enzyme. Bacterial engineering could be utilized to design improved protein drugs for hypertension and heart failure.