Molecular Pharmacology Unit, Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology Zurich Zurich, Switzerland.
Front Physiol. 2013 Jun 19;4:148. doi: 10.3389/fphys.2013.00148. eCollection 2013.
Reactive oxygen species (ROS) is a significant feature of atherosclerosis but the impact of ROS on atherogenesis is not clear since antioxidants such as vitamin E have little effect on atherosclerosis development in vivo. To investigate the role of ROS in atherosclerosis, we used ApoE-deficient mice, and compared the treatment effect of the antioxidant vitamin E with that of the angiotensin-converting enzyme (ACE) inhibitor, captopril, because angiotensin II is a major source of ROS in the vasculature. Dihydroethidium (DHE) staining demonstrated that vitamin E and captopril both prevented the atherosclerosis-induced increase in aortic superoxide content. In contrast, seven months of vitamin E treatment retarded the development of atherosclerotic lesions by only 45.8 ± 11.5% whereas captopril reduced the aortic plaque area by 88.1 ± 7.5%. To discriminate between vitamin E-sensitive and -insensitive effects of ACE inhibition, we performed whole genome microarray gene expression profiling. Gene ontology (GO) and immunohistology analyses showed that vitamin E and captopril prevented atherosclerosis-related changes of aortic intima and media genes. However, vitamin E did not reduce the expression of probe sets detecting the aortic recruitment of pro-inflammatory immune cells while immune cell-specific genes were normalized by captopril treatment. Moreover, vitamin E did not prevent the atherosclerosis-dependent down-regulation of perivascular nerve-specific genes, which were preserved in captopril-treated aortas. Taken together, our study detected antioxidant vitamin E-like effects of angiotensin II inhibition in atherosclerosis treatment regarding preservation of aortic intima and media genes. Additional vitamin E-insensitive effects targeting atherosclerosis-enhancing aortic immune cell recruitment and perivascular nerve degeneration could account for the stronger anti-atherogenic activity of ACE inhibition compared to vitamin E.
活性氧（ROS）是动脉粥样硬化的一个重要特征，但 ROS 对动脉粥样硬化形成的影响尚不清楚，因为抗氧化剂如维生素 E 对体内动脉粥样硬化的发展几乎没有影响。为了研究 ROS 在动脉粥样硬化中的作用，我们使用了载脂蛋白 E 缺陷小鼠，并比较了抗氧化维生素 E 与血管紧张素转换酶（ACE）抑制剂卡托普利的治疗效果，因为血管紧张素 II 是血管中 ROS 的主要来源。二氢乙啶（DHE）染色表明，维生素 E 和卡托普利均可预防动脉粥样硬化诱导的主动脉超氧含量增加。相比之下，7 个月的维生素 E 治疗仅使动脉粥样硬化病变的发展延缓了 45.8±11.5%，而卡托普利则使主动脉斑块面积减少了 88.1±7.5%。为了区分 ACE 抑制的维生素 E 敏感和不敏感作用，我们进行了全基因组微阵列基因表达谱分析。基因本体论（GO）和免疫组织化学分析表明，维生素 E 和卡托普利可预防主动脉内膜和中膜与动脉粥样硬化相关的基因变化。然而，维生素 E 并未降低检测主动脉募集促炎免疫细胞的探针集的表达，而免疫细胞特异性基因在卡托普利治疗后被归一化。此外，维生素 E 不能预防动脉粥样硬化依赖性的血管周围神经特异性基因下调，而在卡托普利处理的主动脉中则保留了这些基因。综上所述，我们的研究在动脉粥样硬化治疗中检测到了血管紧张素 II 抑制的抗氧化维生素 E 样作用，可维持主动脉内膜和中膜基因。针对增强动脉粥样硬化的主动脉免疫细胞募集和血管周围神经退化的维生素 E 不敏感作用可能是 ACE 抑制比维生素 E 具有更强的抗动脉粥样硬化活性的原因。
