EFFECT OF PROBUCOL ON LDL OXIDATION AND ATHEROSCLEROSIS IN LDL RECEPTOR-DEFICIENT MICE

Probucol is a powerful inhibitor of atherosclerosis in a number of ani mal models. However, it is unknown whether this is due to the strong a ntioxidant protection of low density lipoprotein (LDL), to antioxidant effects in the artery wall, or to cellular effects not shared by othe r antioxidants. To investigate whether murine models are suitable to s tudy the antiatherogenic mechanisms of probucol, three experiments fol lowing different protocols were carried out in 135 male and female LDL receptor-deficient (LDLR-/-) mice, Treatment groups received a high ( 0.5%) or low (0.025%) dose of probucol, or low-dose probucol plus a hi gh dose (0.1%) of vitamin E for periods ranging from 6 to 26 weeks. In all experiments, probucol strongly protected LDL against ex vivo oxid ation (lag times exceeding 1400 min in 0.5% probucol-treated mice). Tr eatment with 0.5% probucol significantly lowered both HDL-cholesterol and plasma apolipoprotein (apo)A-I concentrations. In all three experi ments, treatment with 0.5% probucol consistently increased the size of lesions in the aortic origin, from 1.3-fold (n.s.) to 2.9-fold (P < 0 .05) in female mice and from 3.6- to 3.7-fold in males (P < 0.001). Ev en treatment with 0.025% probucol increased atherosclerosis 1.6-fold i n male mice (P < 0.01), Addition of the high dose of vitamin E did not attenuate the pro-atherogenic effect of 0.025% probucol, In conclusio n, probucol not only failed to decrease but actively increased atherog enesis in LDLR-/- mice in a dose-dependent manner, even though it prov ided a very strong antioxidant protection of LDL.ir This suggests that the reduction of atherosclerosis observed in other animal models is d ue to intracellular effects of probucol not found in mice, to differen ces in the metabolism of probucol, and/or to an overriding atherogenic effect of the decrease in HDL in murine models.