Tissue Angiotensin-Converting-Enzyme (ACE) Deficiency Leads to a Reduction in Oxidative Stress and in Atherosclerosis

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Abstract
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 0 ) 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 0 mice, resulting in atherosclerotic mice heterozygous for ACE (ACE +/− /E 0 mice), exhibited reduced lipid peroxidation, increased paraoxonase activity, and lower macrophage LDL oxidation compared with E 0 and ACE +/+ /E 0 mice. ACE +/− /E 0 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 0 mice. Finally, 2 animals genotyped as homozygous-knockout for both ACE and APOE genes (ACE − / − /E 0 ), exhibited a striking reduction of 86% in their atherosclerotic lesion area compared with E 0 mice. Conclusions— Reduction of tissue ACE with the ACE-knockout mouse type-2 model inhibited oxidative stress and atherogenesis.

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