INHIBITION OF HYPERCHOLESTEROLEMIA-INDUCED ATHEROSCLEROSIS IN THE NONHUMAN PRIMATE BY PROBUCOL .1. IS THE EXTENT OF ATHEROSCLEROSIS RELATED TO RESISTANCE OF LDL TO OXIDATION
INHIBITION OF HYPERCHOLESTEROLEMIA-INDUCED ATHEROSCLEROSIS IN THE NONHUMAN PRIMATE BY PROBUCOL .1. IS THE EXTENT OF ATHEROSCLEROSIS RELATED TO RESISTANCE OF LDL TO OXIDATION
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DOI：
10.1172/jci117301
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发表时间：
1994-07-01
影响因子：
15.9
通讯作者：
ROSS, R
中科院分区：
文献类型：
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作者：
SASAHARA, M;RAINES, EW;ROSS, R
脂蛋白氧化被认为在动脉粥样硬化形成中起重要作用。为了研究抑制低密度脂蛋白（LDL）的氧化是否会改变非人灵长类动物的动脉粥样硬化形成，我们给食高脂肪、高胆固醇饮食的猕猴服用了普罗布考（一种有效的抗氧化剂）。在开始高胆固醇饮食后14周，对16只猴子中的一半给予普罗布考，每天给予普罗布考，直到11个月后处死。为了评价普罗布考的抗氧化作用，评价了分离的血浆LDL对体外氧化的抗性。普罗布考显着增加了LDL的抗氧化修饰，所示的共轭二烯形成所需的滞后时间的增加。普罗布考治疗的动物中的病变似乎不太成熟，并且在平滑肌细胞中观察到脂质积累增加。比较所有对照组和普罗布考治疗组猴子，发现普罗布考治疗组猴子胸主动脉内膜病变面积减少了43%（P < 0.0001），但在腹主动脉或髂动脉病变面积上没有发现显著差异。然而，在8只普罗布考治疗的动物中，有2只的共轭二烯形成的滞后期没有延长。所有16只动物的内膜病变尺寸与滞后期的曲线图显示，病变尺寸与所有解剖部位的抗氧化性呈负相关趋势。内膜病变大小与LDL抗氧化性之间的强负相关性支持脂蛋白氧化在动脉粥样硬化病变的发展和进展中的作用。不能排除某些效应是由于普罗布考的其他生物学特性的可能性。
Lipoprotein oxidation is believed to play an important role in atherogenesis. To investigate whether inhibition of oxidation of low density lipoprotein (LDL) would alter atherogenesis in the nonhuman primate, we administered probucol, a potent antioxidant, to Macaca nemestrina fed a high-fat, high-cholesterol diet. Probucol was administered to half of the 16 monkeys 14 wk after starting the hypercholesterolemic diet, and was given daily until they were sacrificed after 11 mos. To evaluate the antioxidant effect of probucol, the resistance of isolated plasma LDL to in vitro oxidation was evaluated. Probucol significantly increased the resistance of LDL to oxidative modification, as shown by an increase in the Lag time required for conjugated diene formation. Lesions in the probucol-treated animals appeared less mature, and increased accumulation of lipid was observed in smooth muscle cells. Comparison of all control and probucol-treated monkeys demonstrated that intimal lesion areas in the thoracic aortas of the probucol-treated monkeys were reduced by 43% (P < 0.0001), but no significant difference in lesion area was found in the abdominal aortas or in the iliac arteries. However, the lag phase of conjugated diene formation was not prolonged in 2 of the 8 probucol-treated animals. A plot of intimal lesion size versus lag phase of all 16 animals showed a trend that lesion size was inversely related to oxidation resistance for all anatomic sites. The strong inverse relationship between intimal lesion size and resistance of LDL to oxidation supports a role for lipoprotein oxidation in the development and progression of lesions of atherosclerosis. The possibility that some of the effect is due to other biological properties of probucol cannot be ruled out.