Effect of probucol on LDL oxidation and atherosclerosis in LDL receptor-deficient mice.

    普罗布考在许多动物模型中是一种抗动脉粥样硬化的强抑制剂。但尚未清楚其抑制作用是否来源于其对低密度脂蛋白（LDL）的强抗氧化保护作用，对动脉壁的抗氧化作用或与其他抗氧化剂不同的对细胞的影响作用。本试验的目的是老鼠是否适合作为研究普罗布考对动脉粥样硬化疗效的动物模型。对135只雌雄LDL受体缺乏（LDLR-/-）小鼠施行3种不同的试验草案。治疗组接受高剂量(0.5%)或低剂量普罗布考(0.025%)或低剂量普罗布考加高剂量维生素E（0.1%）治疗6到26周。在所有的试验中，普罗布考能够强烈保护LDL的体外氧化（在0.5%普罗布考治疗延迟时间超过1400分钟）。0.5%普罗布考能够显著降低HDL胆固醇和血浆载脂蛋白（apo）A-I的浓度。三组试验中，0.5%普罗布考能够持续增加大动脉损伤面积，雌鼠增为1.3倍到2.9倍(P < 0.05)，雄鼠增为3.6到3.7倍(P < 0.001)。即使0.025%普罗布考仍能增加雄性小鼠的动脉粥样硬化1.6倍。与高剂量维生素E合用不能削弱0.025%普罗布考的致动脉粥样硬化作用。总之，尽管普罗布考对LDL有强抗氧化作用，但其不仅不能降低反而增加LDLR-/-缺陷小鼠动脉粥样硬化的发生。提示普罗布考在其他动物模型中观察到的抗动脉粥样硬化作用与LDLR-/-缺陷小鼠体内为观察到的细胞内作用，普罗布考不同的代谢机制，和/或小鼠模型中HDL降低引起的重要致动脉粥样硬化有关。

    Probucol is a powerful inhibitor of atherosclerosis in a number of animal models. However, it is unknown whether this is due to the strong antioxidant protection of low density lipoprotein (LDL), to antioxidant effects in the artery wall, or to cellular effects not shared by other antioxidants. To investigate whether murine models are suitable to study the  antiatherogenic mechanisms of probucol, three experiments following 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 high dose (0.1%) of vitamin E for periods ranging from 6 to 26 weeks. In all experiments,     probucol strongly protected LDL against ex vivo oxidation (lag times exceeding 1400 min in 0.5% probucol-treated mice).  Treatment with 0.5% probucol significantly lowered both HDL-cholesterol and plasma apolipoprotein(apo)A-I concentrations. In all three experiments, 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). Even treatment with 0.025% probucol increased atherosclerosis 1.6-fold in 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 conclusion, probucol not only failed to decrease but actively increased atherogenesis in LDLR-/- mice in a dose-dependent manner,even though it provided a very strong        antioxidant protection of LDL. This suggests that the reduction of atherosclerosis observed in other animal models is due to intracellular effects of probucol not found in mice, to differences in the metabolism of probucol, and/or to an       overriding atherogenic effect of the decrease in HDL in murine models.