Increased Angiotensin II–Induced Hypertension and Inflammatory Cytokines in Mice Lacking Angiotensin-Converting Enzyme N Domain Activity

• Published in: Hypertension (Dallas, Tex. 1979) Tex. 1979), 2012-02, Vol.59 (2), p.283-290
• Main Authors: Ong, Frank S, Lin, Chentao X, Campbell, Duncan J, Okwan-Duodu, Derick, Chen, Xu, Blackwell, Wendell-Lamar B, Shah, Kandarp H, Gonzalez-Villalobos, Romer A, Shen, Xiao Z, Fuchs, Sebastien, Bernstein, Kenneth E
• Format: Article
• Language: English
• Subjects: Angiotensin II - adverse effects; Animals; Arterial hypertension. Arterial hypotension; Biological and medical sciences; Blood and lymphatic vessels; Blood Pressure - physiology; Cardiology. Vascular system; Clinical manifestations. Epidemiology. Investigative techniques. Etiology; Cytokines - metabolism; Disease Models, Animal; Hypertension - chemically induced; Hypertension - metabolism; Hypertension - physiopathology; Macrophages - metabolism; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Peptidyl-Dipeptidase A - deficiency; Peptidyl-Dipeptidase A - genetics; Protein Structure, Tertiary; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/HYPERTENSIONAHA.111.180844

—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.