Document Detail

Increased angiotensin II-induced hypertension and inflammatory cytokines in mice lacking angiotensin-converting enzyme N domain activity.
MedLine Citation:
PMID:  22203735     Owner:  NLM     Status:  MEDLINE    
-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.
Frank S Ong; Chentao X Lin; Duncan J Campbell; Derick Okwan-Duodu; Xu Chen; Wendell-Lamar B Blackwell; Kandarp H Shah; Romer A Gonzalez-Villalobos; Xiao Z Shen; Sebastien Fuchs; Kenneth E Bernstein
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-12-27
Journal Detail:
Title:  Hypertension     Volume:  59     ISSN:  1524-4563     ISO Abbreviation:  Hypertension     Publication Date:  2012 Feb 
Date Detail:
Created Date:  2012-01-25     Completed Date:  2012-04-20     Revised Date:  2014-09-24    
Medline Journal Info:
Nlm Unique ID:  7906255     Medline TA:  Hypertension     Country:  United States    
Other Details:
Languages:  eng     Pagination:  283-90     Citation Subset:  IM    
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MeSH Terms
Angiotensin II / adverse effects*
Blood Pressure / physiology
Cytokines / metabolism*
Disease Models, Animal
Hypertension / chemically induced*,  metabolism,  physiopathology*
Macrophages / metabolism
Mice, Inbred C57BL
Mice, Knockout
Peptidyl-Dipeptidase A / deficiency*,  genetics
Protein Structure, Tertiary
Tumor Necrosis Factor-alpha / metabolism
Grant Support
F32 HL105036/HL/NHLBI NIH HHS; F32 HL105036/HL/NHLBI NIH HHS; F32 HL105036-01A1/HL/NHLBI NIH HHS; F32 HL105036-02/HL/NHLBI NIH HHS; K99 DK083455/DK/NIDDK NIH HHS; K99 DK083455/DK/NIDDK NIH HHS; K99 DK083455-02/DK/NIDDK NIH HHS; K99 HL088000/HL/NHLBI NIH HHS; K99 HL088000/HL/NHLBI NIH HHS; K99 HL088000-02/HL/NHLBI NIH HHS; R01 DK039777/DK/NIDDK NIH HHS; R01 DK039777/DK/NIDDK NIH HHS; R01 DK039777-24/DK/NIDDK NIH HHS; R01 HL110353/HL/NHLBI NIH HHS; R01 HL110353/HL/NHLBI NIH HHS; R01 HL110353-25/HL/NHLBI NIH HHS; T32 DK007770/DK/NIDDK NIH HHS; T32 DK007770/DK/NIDDK NIH HHS; T32 DK007770-09/DK/NIDDK NIH HHS; T32 DK007770-10/DK/NIDDK NIH HHS
Reg. No./Substance:
0/Cytokines; 0/Tumor Necrosis Factor-alpha; 11128-99-7/Angiotensin II; EC A

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