Site-Specific Antiatherogenic Effect of Probucol in Apolipoprotein E–Deficient Mice

Abstract

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.

Chronic Renal Failure Accelerates Atherogenesis in Apolipoprotein E–Deficient Mice

“…This suggests that uremia in apo-E Ϫ/Ϫ mice affects lesion formation differently in the aortic root compared with the thoracic and abdominal parts of the aorta. Differential atherogenic responses to treatment in different parts of the aorta have been observed previously in mice, e.g., lesion size increased in the aortic root whereas lesion involvement decreased in the thoracic aorta in probucol-treated apo-E Ϫ/Ϫ mice and in bone marrow-transplanted LDL receptor-deficient mice (32,33). The present results underscore the importance of using more than one measure of atherosclerosis in mouse studies in general and in studies of CRF effects in the apo-E Ϫ/Ϫ mouse in particular.…”

Myriocin slows the progression of established atherosclerotic lesions in apolipoprotein E gene knockout mice

“…Interestingly, myriocin inhibited the progression of atherosclerotic lesions effectively only at the distal regions of the aorta. At present, the reasons for this site-specific action are unclear; however, this may be a general phenomenon associated with the pharmacological treatment of apoE 2/2 mice, since the antiatherogenic actions of other compounds, such as vitamin E plus coenzyme Q 10 (34) and probucol (35), are also more potent at the distal lesion sites.…”

Assessment of Myeloperoxidase Activity by the Conversion of Hydroethidine to 2-Chloroethidium

“…Vessels were fixed in situ by pressure perfusion fixation at 100 mm Hg with 10% neutral buffered formalin through the left ventricle (30). Both left and right femoral arteries were harvested, placed in 10% formalin overnight, and then stored in 70% (v/v) ethanol.…”