Processes involved in the site-specific effect of probucol on atherosclerosis in apolipoprotein E gene knockout mice

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 ( alpha- 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 alpha- tocopherol, and decreased concentrations of oxidized lipids ( cholesteryl ester hydroperoxides, F-2- 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.