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-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.