on October 2, 2003
Published online before print October 2, 2003, doi: 10.1161/01.ATV.0000098653.74209.C6
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Submitted on June 3, 2003
Accepted on July 28, 2003
Tissue Angiotensin-Converting-Enzyme (ACE) Deficiency Leads to a Reduction in Oxidative Stress and in Atherosclerosis. Studies in ACE-Knockout Mice Type 2
Tony Hayek *;
From the Lipid Research Laboratory (T.H., E.P., S.H., S.K., M.A., M.K.) and Department of Anatomy and Cell Biology (R.C.), Bruce Rappaport Faculty of Medicine, Technion, Rappaport Institute for Research in the Medical Sciences, Rambam Medical Center, Haifa, Israel.
* To whom correspondence should be addressed. E-mail: -t_hayek{at}rambam.health.gov.il.
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 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.
Key words: angiotensin-converting enzyme • atherosclerosis • knockout mice • lipoproteins
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