Tissue angiotensin-converting-enzyme (ACE) deficiency leads to a reduction in oxidative stress and in atherosclerosis: studies in ACE-knockout mice type 2.

UNLABELLED Background- Angiotensin II, produced by angiotensin-converting-enzyme (ACE), enhances oxidative stress and atherogenesis. In this study, we analyzed whether tissue ACE deficiency in ACE-knockout mice type-2 would affect their oxidative status. Moreover, by crossbreeding the ACE-knockout mice with atherosclerotic apolipoprotein E (apo E)-deficient (E0) mice, we questioned whether tissue ACE deficiency affects atherogenesis. METHODS AND RESULTS ACE-deficient mice type-2 (ACE+/-) exhibited reduced serum lipid peroxidation compared with ACE+/+ mice. Peritoneal macrophages from ACE+/- mice demonstrated lower oxidative status, as exhibited by decreases of 47%, 33% 56%, and 51%, in their lipid peroxides, superoxide release, dichlorofluorescein fluorescence, and LDL oxidation, respectively, compared with ACE+/+ mice. ACE+/- mice crossbred with E0 mice, resulting in atherosclerotic mice heterozygous for ACE (ACE+/-/E0 mice), exhibited reduced lipid peroxidation, increased paraoxonase activity, and lower macrophage LDL oxidation compared with E0 and ACE+/+/E0 mice. ACE+/-/E0 mice also exhibited reduced NADPH-induced aortic superoxide ion production by 52% and a reduction of 43% in their atherosclerotic lesion size compared with E0 mice. Finally, 2 animals genotyped as homozygous-knockout for both ACE and APOE genes (ACE-/-/E0), exhibited a striking reduction of 86% in their atherosclerotic lesion area compared with E0 mice. CONCLUSIONS Reduction of tissue ACE with the ACE-knockout mouse type-2 model inhibited oxidative stress and atherogenesis.