Hayek Tony, Pavlotzky Elsa, Hamoud Shadi, Coleman Raymond, Keidar Shlomo, Aviram Michael, Kaplan Marielle
Lipid Research Laboratory, Bruce Rappaport Faculty of Medicine, Technion, Rappaport Institute for Research in the Medical Sciences, Rambam Medical Center, Haifa, Israel.
Arterioscler Thromb Vasc Biol. 2003 Nov 1;23(11):2090-6. doi: 10.1161/01.ATV.0000098653.74209.C6. Epub 2003 Oct 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 (E0) mice, we questioned whether tissue ACE deficiency affects atherogenesis.
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.
Reduction of tissue ACE with the ACE-knockout mouse type-2 model inhibited oxidative stress and atherogenesis.
背景-血管紧张素转换酶（ACE）产生的血管紧张素II可增强氧化应激和动脉粥样硬化形成。在本研究中，我们分析了2型ACE基因敲除小鼠的组织ACE缺乏是否会影响其氧化状态。此外，通过将ACE基因敲除小鼠与动脉粥样硬化载脂蛋白E（apo E）缺陷（E0）小鼠杂交，我们探究了组织ACE缺乏是否会影响动脉粥样硬化形成。
与ACE+/+小鼠相比，2型ACE缺陷小鼠（ACE+/-）的血清脂质过氧化水平降低。ACE+/-小鼠的腹腔巨噬细胞氧化状态较低，与ACE+/+小鼠相比，其脂质过氧化物、超氧化物释放、二氯荧光素荧光和低密度脂蛋白（LDL）氧化分别降低了47%、33%、56%和51%。与E0和ACE+/+/E0小鼠相比，ACE+/-小鼠与E0小鼠杂交产生的杂合ACE基因动脉粥样硬化小鼠（ACE+/-/E0小鼠）脂质过氧化水平降低，对氧磷酶活性增加，巨噬细胞LDL氧化水平降低。与E0小鼠相比，ACE+/-/E0小鼠NADPH诱导的主动脉超氧阴离子产生也减少了52%，动脉粥样硬化病变大小减少了43%。最后，2只同时被基因分型为ACE和APOE基因纯合敲除的动物（ACE-/-/E0），与E0小鼠相比，其动脉粥样硬化病变面积显著减少了86%。
2型ACE基因敲除小鼠模型中组织ACE的减少抑制了氧化应激和动脉粥样硬化形成。
