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 Ϫ/Ϫ ) mice.
Methods and Results-Male apoEϪ/Ϫ 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 (␣-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 ␣-tocopherol, and decreased concentrations of oxidized lipids (cholesteryl ester hydroperoxides, F 2 -isoprostanes, and 7-ketocholesterol).
Conclusions-Probucol affects atherosclerosis in apoEϪ/Ϫ 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. Key Words: antioxidants Ⅲ atherosclerosis Ⅲ collagen Ⅲ free radicals Ⅲ inflammation A therosclerosis represents a state of heightened oxidative stress characterized by lipid and protein oxidation in the vascular wall. 1 The oxidative modification hypothesis of atherosclerosis predicts that low-density lipoprotein (LDL) oxidation is an early event in and that oxidized LDL contributes to atherogenesis. 2 Oxidized LDL supports foam cell formation in vitro and other potentially pro-atherogenic activities, the lipid in human lesions is oxidized and contains oxidized LDL, and several different antioxidants inhibit atherosclerosis in animals. 1 In addition to LDL oxidation, other relevant oxidative events include the production of reactive oxygen and nitrogen species by vascular cells, 3 and oxidative modifications contributing to important clinical manifestations of coronary artery disease such as endothelial dysfunction and plaque disruption. 1 However, despite abundant data, fundamental problems remain with implicating oxidative modification as a requisite cause for atherosclerosis. 1 These include the poor performance of antioxidants in limiting atherosclerosis or cardiovascular events from it, 4 and observations in animals that suggest dissociation between atherosclerosis and lipoprotein lipid oxidation. [5][6][7][8][9] To reconcile these discrepancies, the "oxidative response to inflammation" model of atherosclerosis 1 considers inflammation as a primary process of atherosclerosis, an...
