Processes Involved in the Site-Specific Effect of Probucol on Atherosclerosis in Apolipoprotein E Gene Knockout Mice

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Abstract
Objective— To elucidate processes by which the antioxidant probucol increases lesion size at the aortic sinus and decreases atherosclerosis at more distal sites in apolipoprotein E–deficient (apoE−/−) mice. Methods and Results— Male apoE−/− mice were fed high-fat chow with 1% (w/w) probucol or without (controls) for 6 months, before aortic sinus, arch, and descending aorta were analyzed separately for lesion size and composition. Compared with control, probucol significantly increased lesion size by 33% at the sinus, but it inhibited atherosclerosis at the descending aorta by 94%. Sites where atherosclerosis was inhibited contained substantially fewer macrophages, less lipids (cholesterol and cholesteryl esters), and endogenous antioxidant (α-tocopherol), but not oxidized lipids, and the extent to which probucol metabolism occurred was increased. Compared with control, aortic sinus lesions of probucol mice contained a substantially increased content of extracellular matrix, but decreased total cell and macrophage density, comparable levels of lipids and α-tocopherol, and decreased concentrations of oxidized lipids (cholesteryl ester hydroperoxides, F2-isoprostanes, and 7-ketocholesterol). Conclusions— Probucol affects atherosclerosis in apoE−/− mice independent of the accumulation of arterial lipid oxidation products, thereby dissociating the 2 processes. Rather, probucol exerts antiinflammatory activity by decreasing accumulation of macrophages in lesions, and it promotes a more stable lesion composition at the aortic sinus. We investigated how the antioxidant probucol increases lesion size at the sinus and decreases atherosclerosis at distal sites in apolipoprotein E-deficient mice. Probucol affected atherosclerosis independent of arterial lipid oxidation. Rather, probucol decreased accumulation of macrophages in lesions, and it promoted a more stable lesion composition at the aortic sinus.