Increased angiotensin II-induced hypertension and inflammatory cytokines in mice lacking angiotensin-converting enzyme N domain activity

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Abstract

Angiotensin-converting enzyme (ACE) is composed of the N-and C-terminal catalytic domains. To study the role of the ACE domains in the inflammatory response, N-knockout (KO) and C-KO mice, models lacking 1 of the 2 ACE domains, were analyzed during angiotensin II-induced hypertension. At 2 weeks, N-KO mice have systolic blood pressures that averaged 173±4.6 mm Hg, which is more than 25 mm Hg higher than the blood pressures observed in wild-type or C-KO mice (146±3.2 and 147±4.2 mm Hg). After 3 weeks, blood pressure differences between N-KO, C-KO, and wild-type were even more pronounced. Macrophages from N-KO mice have increased expression of tumor necrosis factor α after stimulation with either lipopolysaccharide (about 4-fold) or angiotensin II (about 2-fold), as compared with C-KO or wild-type mice. Inhibition of the enzyme prolyl oligopeptidase, responsible for the formation of acetyl-SerAspLysPro and other peptides, eliminated the blood pressure difference and the difference in tumor necrosis factor α expression between angiotensin II-treated N-KO and wild-type mice. However, this appears independent of acetyl-SerAspLysPro. These data establish significant differences in the inflammatory response as a function of ACE N-or C-domain catalytic activity. They also indicate a novel role of prolyl oligopeptidase in the cytokine regulation and in the blood pressure response to experimental hypertension. © 2011 American Heart Association, Inc..

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Ong, F. S., Lin, C. X., Campbell, D. J., Okwan-Duodu, D., Chen, X., Blackwell, W. L. B., … Bernstein, K. E. (2012). Increased angiotensin II-induced hypertension and inflammatory cytokines in mice lacking angiotensin-converting enzyme N domain activity. Hypertension, 59(2), 283–290. https://doi.org/10.1161/HYPERTENSIONAHA.111.180844

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