PARADOXICAL ENHANCEMENT OF ATHEROSCLEROSIS BY PROBUCOL TREATMENT IN APOLIPOPROTEIN E-DEFICIENT MICE

Dietary administration of probucol (0.5%, wt/wt) efficiently reduced t otal plasma cholesterol levels in apolipoprotein E-deficient mice (apo E-/-) by 40%, with decreases in high density lipoprotein (HDL) and apo AI by 70 and 50%, respectively. Paradoxically, however, aortic atheros clerotic plaques in the probucol-treated apoE-/- mice formed more rapi dly than in the untreated apoE-/- mice, and the lesions were two to fo ur times larger and more mature regardless of sex, age, and genetic ba ckground (P < 10(-6)). Histologically, lesions in probucol-treated mic e contained increased fibrous materials and cells other than foam cell s, and were commonly associated with focal inflammation and aneurysmal dilatation. Probucol treatment also accelerated lesion development in apoE+/- mice fed an atherogenic diet, indicating that the adverse eff ect is not dependent on the complete absence of apoE. Furthermore, mic e lacking apoE and apoAI have plasma lipoprotein profiles very similar to the probucol-treated apoE-/- mice, but do not have accelerated pla que development. Thus, the enhanced atherosclerosis in the probucol-tr eated animals is unlikely to be caused by the reduction of HDL and apo AI levels. Our data indicate that a reduction in plasma cholesterol ca used by probucol does not necessarily lead to an antiatherogenic effec t.