Abstract-Intimal oxidation of LDL is considered an important early event in atherogenesis, and certain antioxidants are antiatherogenic. Dietary coenrichment with vitamin E (VitE) plus ubiquinone-10 (CoQ 10 , which is reduced during intestinal uptake to the antioxidant ubiquinol-10, CoQ 10 H 2 ) protects, whereas enrichment with VitE alone can increase oxidizability of LDL lipid against ex vivo oxidation. In the present study, we tested whether VitE plus CoQ 10 cosupplementation is more antiatherogenic than either antioxidant alone, by use of apolipoprotein E-deficient (apoEϪ/Ϫ) mice fed a high-fat diet without (control) or with 0.2% (wt/wt) VitE, 0.5% CoQ 10 , or 0.2% VitE plus 0.5% CoQ 10 (VitEϩCoQ 10 ) for 24 weeks. None of the supplements affected plasma cholesterol concentrations, whereas in the VitE and CoQ 10 groups, plasma level of the respective supplement increased. Compared with control, plasma from CoQ 10 or VitEϩCoQ 10 but not VitE-supplemented animals was more resistant to ex vivo lipid peroxidation induced by peroxyl radicals. VitE supplementation increased VitE levels in aorta, heart, brain, and skeletal muscle, whereas CoQ 10 supplementation increased CoQ 10 only in plasma and aorta and lowered tissue VitE. All treatments significantly lowered aortic cholesterol compared with control, but only VitEϩCoQ 10 supplementation significantly decreased tissue lipid hydroperoxides when expressed per parent lipid. In contrast, none of the treatments affected aortic ratios of 7-ketocholesterol to cholesterol. Compared with controls, VitEϩCoQ 10 supplementation decreased atherosclerosis at the aortic root and arch and descending thoracic aorta to an extent that increased with increasing distance from the aortic root. CoQ 10 significantly inhibited atherosclerosis at aortic root and arch, whereas VitE decreased disease at aortic root only. Thus, in apoEϪ/Ϫ mice, VitEϩCoQ 10 supplements are more antiatherogenic than CoQ 10 or VitE supplements alone and disease inhibition is associated with a decrease in aortic lipid hydroperoxides but not 7-ketocholesterol.
Abstract-The lipid-lowering antioxidant probucol can inhibit atherosclerosis in animals and restenosis in humans.However, probucol has been shown to promote atherosclerosis in the aortic root of apolipoprotein E-deficient (apoEϪ/Ϫ) mice. In the current study, we examined the effects of probucol on both lesion formation at 4 sites along the aorta and lipoprotein oxidation in the plasma and aortas of apoEϪ/Ϫ mice receiving a diet containing 21.2% (wt/wt) fat and 0.15% (wt/wt) cholesterol without or with 1% (wt/wt) probucol. After 6 months, controls had developed lesions at all sites investigated. Lesion development was strongly (Pϭ0.0001) affected by probucol, but this effect was not uniform: lesion size was increased in the aortic root but significantly decreased in the arch, the descending thoracic aorta, and proximal abdominal aorta. Plasma and aortas of probucol-treated mice contained high concentrations of probucol and its metabolites (bisphenol and diphenoquinone); increased vitamin C; markedly decreased very low density lipoprotein (but not low density lipoprotein and high density lipoprotein); and decreased cholesterol, cholesteryl esters, triglycerides, vitamin E, and oxidized lipids compared with controls. Interestingly, probucol treatment did not decrease the proportion of aortic lipids that were oxidized. Plasma vitamin C and bisphenol, but not probucol, protected plasma lipids from ex vivo oxidation by peroxyl radicals. These results show that as in other species, probucol can inhibit lesion formation in most parts of the aorta of apoEϪ/Ϫ mice. This effect may involve lipid oxidation-independent mechanisms localized within the vessel wall as well as lipid lowering.
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