Differential ANG II generation in plasma and tissue of mice with decreased expression of the ACE gene.
We utilized mice with homozygous disruption of angiotensin-converting enzyme (ACE) (-/-), mice with heterozygous deletion of ACE (+/-), and wild-type mice (+/+) to test the hypothesis that genetic variation in ACE modulates tissue and plasma angiotensin (ANG) II concentrations. With the use of ANG I as substrate, kidney, heart, and lung ACE activity was reduced 80% in -/- mice compared with +/+ mice. However, ANG II concentrations and ANG II-to-ANG I ratios in the kidney, heart, and lung did not differ among genotypes. In contrast, plasma ANG II concentrations in -/- mice were <2 fmol/ml, whereas plasma ANG I concentrations were extremely high (765 fmol/ml). Chymase activity was increased 14-fold in the kidney (P < 0.05) and 1.5-fold in the heart (P < 0.05) of -/- versus +/+ mice but did not differ among genotypes in the lung. ANG II formation from enzymes other than ACE and chymase contributed <2% of total ANG II formation in all genotypes. These data suggest that ACE is essential to ANG II formation in the vascular space, whereas chymase may provide an important mechanism in maintaining steady-state ANG II levels in tissue.
Wei
Chih-Chang
CC
Birmingham Veteran Affairs Medical Center and Division of Cardiovascular Disease, Department of Medicine, Vascular Biology and Hypertension Program, University of Alabama, Birmingham, Alabama 35294, USA.
Tian
Baohong
B
Perry
Gilbert
G
Meng
Qing Cheng
QC
Chen
Yiu-Fai
YF
Oparil
Suzanne
S
Dell'Italia
Louis J
LJ
D000803:Angiotensin I / Q000097:blood / Q000378:metabolism; D000804:Angiotensin II / Q000097:blood / Q000378:metabolism*; D000818:Animals; D053818:Chymases; D015870:Gene Expression; D007668:Kidney / Q000201:enzymology; D007700:Kinetics; D008168:Lung / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016254:Mutagenesis, Insertional; D009206:Myocardium / Q000201:enzymology; D007703:Peptidyl-Dipeptidase A / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism
D000804:Angiotensin II; D000803:Angiotensin I; D007703:Peptidyl-Dipeptidase A; D012697:Serine Endopeptidases; D053818:Chymases