Tissue Angiotensin-Converting-Enzyme (ACE) Deficiency Leads to a Reduction in Oxidative Stress and in Atherosclerosis: Studies in ACE-Knockout Mice Type 2

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 (E) 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 E mice, resulting in atherosclerotic mice heterozygous for ACE (ACE/E mice), exhibited reduced lipid peroxidation, increased paraoxonase activity, and lower macrophage LDL oxidation compared with E and ACE/E mice. ACE/E mice also exhibited reduced NADPH-induced aortic superoxide ion production by 52% and a reduction of 43% in their atherosclerotic lesion size compared with E mice. Finally, 2 animals genotyped as homozygous-knockout for both ACE and APOE genes (ACE/E), exhibited a striking reduction of 86% in their atherosclerotic lesion area compared with E mice. CONCLUSIONS—Reduction of tissue ACE with the ACE-knockout mouse type-2 model inhibited oxidative stress and atherogenesis.