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

ABSTRACT: 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.

SUBMITTER: Minato T

PROVIDER: S-EPMC7044196 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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

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

Nature communications 20200226 1

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 th ...[more]

PMID: 32103002

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Project description:Air pollution, via ambient PM2.5, is a big threat to public health since it associates with increased hospitalisation, incidence rate and mortality of cardiopulmonary injury. However, the potential mediators of pulmonary injury in PM2.5 -induced cardiovascular disorder are not fully understood. To investigate a potential cross talk between lung and heart upon PM2.5 exposure, intratracheal instillation in vivo, organ culture ex vivo and human bronchial epithelial cells (Beas-2B) culture in vitro experiments were performed respectively. The exposed supernatants of Beas-2B were collected to treat primary neonatal rat cardiomyocytes (NRCMs). Upon intratracheal instillation, subacute PM2.5 exposure caused cardiac dysfunction, which was time-dependent secondary to lung injury in mice, thereby demonstrating a cross-talk between lungs and heart potentially mediated via small extracellular vesicles (sEV). We isolated sEV from PM2.5 -exposed mice serum and Beas-2B supernatants to analyse the change of sEV subpopulations in response to PM2.5 . Single particle interferometric reflectance imaging sensing analysis (SP-IRIS) demonstrated that PM2.5 increased CD63/CD81/CD9 positive particles. Our results indicated that respiratory system-derived sEV containing miR-421 contributed to cardiac dysfunction post-PM2.5 exposure. Inhibition of miR-421 by AAV9-miR421-sponge could significantly reverse PM2.5 -induced cardiac dysfunction in mice. We identified that cardiac angiotensin converting enzyme 2 (ACE2) was a downstream target of sEV-miR421, and induced myocardial cell apoptosis and cardiac dysfunction. In addition, we observed that GW4869 (an inhibitor of sEV release) or diminazene aceturate (DIZE, an activator of ACE2) treatment could attenuate PM2.5 -induced cardiac dysfunction in vivo. Taken together, our results suggest that PM2.5 exposure promotes sEV-linked miR421 release after lung injury and hereby contributes to PM2.5 -induced cardiac dysfunction via suppressing ACE2.

Dataset Information

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

Publications

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

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