Abstract
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.
Highlights
Increased generation of reactive oxygen species (ROS) is a prominent feature of atherosclerosis development (Steinberg et al, 1989; Ross, 1999)
In agreement with previous data (Abd Alla et al, 2010), angiotensin II inhibition by captopril had largely prevented the development of atherosclerotic plaques of ApoE−/− mice (Figure 1A), i.e., the atherosclerotic plaque area was reduced by 88.1 ± 7.5% in captopril-treated mice compared to untreated ApoE−/− mice (Figure 1B)
We focused on those 48 probe sets, which were normalized toward B6 control level, to gain insight into mechanisms underlying the antioxidantsensitive component of atherosclerosis treatment by the angiotensin-converting enzyme (ACE) inhibitor captopril
Summary
Increased generation of reactive oxygen species (ROS) is a prominent feature of atherosclerosis development (Steinberg et al, 1989; Ross, 1999). Inhibition of angiotensin II generation or angiotensin II AT1 receptor antagonism/deficiency retarded the development of atherosclerosis in animal models of atherosclerosis and patients with cardiovascular disease (Hayek et al, 1998; Yusuf et al, 2000; Abd Alla et al, 2004; Wassmann et al, 2004). Many studies confirmed that antioxidants had the potential to decrease the generation of ROS in vitro and in vivo (Ozer et al, 1993; Suarna et al, 1993; Pratico et al, 1998; Thomas et al, 2001; Gavrila et al, 2005) In view of those conflicting results between cellular and animal models, and clinical studies, the impact of ROS on the pathogenesis of atherosclerosis is still not clear
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