普罗布考对高脂家兔胸主动脉内皮储备功能的影响及其机制的探讨
复旦大学附属中山医院，上海市心血管病研究所
赵刚 周京敏 李双杰 卜丽萍 章朝霞 张新刚 王时俊 李高平 葛均波
摘要
目的：探讨口服普罗布考能否改善高胆固醇血症和动脉粥样硬化兔主动脉的内皮储备功能及其可能的机制。方法：将26只新西兰白兔(1.5-2.5kg/只)随机分为3组:正常对照组(普通饮食，ｎ=6)、高脂饮食组(高脂饮食，ｎ=10)、普罗布考治疗组(高脂饮食+普罗布考200mg/kg，ｎ=10)。在高脂饲养前和饲养后第12周，抽血测血清总胆固醇浓度。第12周后处死动物，取胸主动脉，一部分检测离体胸主动脉环对乙酰胆碱(Ach)的反应，另一部分利用RT-PCR技术检测凝集素样氧化低密度脂蛋白受体1（LOX-1）基因表达量。结果:①普罗布考有降血脂作用（39.1%）；②高脂血症兔胸主动脉对乙酰胆碱引起的内皮依赖性舒张(EDR)反应明显降低，普罗布考能明显保护高胆固醇血症所损伤的EDR反应；③3组对硝普钠所致的非内皮依赖性舒张反应均没有差别。④高脂饮食组LOX-1与GAPDH条带面积积分比值明显高于正常饮食组(0.64±0.224vs0.05±0.021, P<0.01)，普罗布考组LOX-1与GAPDH条带面积积分比值明显低于高脂饮食组(0.18±0.061vs0.64±0.224, P<0.01)。 结论：普罗布考能保护高脂家兔胸主动脉内皮储备功能，其机制可能与抗氧化抑制氧化型低密度脂蛋白（ox-LDL）生成及下调LOX-1基因表达量有关。
[关键词]　高胆固醇血症;　普罗布考;　内皮储备功能；凝集素样氧化低密度脂蛋白受体1；兔

Protection of probucol on endothelial dysfunction of HCHF-diet rabbits and the study of the possible mechanism  Zhao gang， Zhou jinming， Li shuangjie， Bu liping， Zhang zhaoxia， Wang shijun， Zhang xinggang， Li gaoping， Ge junpo.  Shanghai Institute of Cardiovascular Diseases Zhongshan Hospital of Fudan University
Abstract    Objective: to observe the effect of probucol on endothelium-dependent vasodilator activity in high cholesterol plus high fat diet (HCHF) rabbits and to explore the possible mechanism. Methods: 26 New Zealand white rabbits(1.5-2.5kg/one) were randomly divided into three groups， that is， control group (n=6， normal diet); hyperlipidemic group (n=10， HCHF-diet); probucol group(n=10， HCHF-diet plus probucol 200mg/kg/d). There blood was drawn from the central ear artery to analyze plasma total cholesterol (TC) at the pre-experiment and in the 12th week of postexperiment. Then all rabbits were killed in the 12th week and  thoracic aortas were isolated to analyze vascular endothelial function and to detect the expression of LOX-1 mRNA by RT-PCR. Results: probucol could remarkably lower plasma TC lever， compared to hyperlipidemic group， TC level decreased 39.1% in probucol group (P<0.01); The HCHF diet significantly attenuated endothelium-dependent relaxation (EDR) of rabbit aortic rings to acetylcholine (Ach)， but probucol could significantly protected against  HCHF diet-injured EDR of rabbit aortic rings; The HCHF diet and probucol did not significantly influence the endothelium-independent relaxation of the rabbit artery elicited by sodium nitroprusside (SNP). Furthermore, very little LOX-1 mRNA expression was showed in normal diet group, which was significantly increased in HCHF diet group and decreased by probucol.  Conclusion: Probucol can attenuate vascular endothelial function through its anti-oxidant effect and the possible mechanism of down regulation of LOX-1 gene expression.

Key words: hypercholesterolemia; probucol; endothelial function; LOX-1; rabbit