普罗布考通过诱导血红素加氧酶1发挥抗动脉粥样硬化作用

目的探讨普罗布考对血红素加氧酶1(HO-1)表达的影响及HO-1在普罗布考抗动脉粥样硬化作用中的地位。方法采用高脂饮食加腹主动脉内膜剥脱术建立兔动脉粥样硬化模型后,60只成模雄性新西兰兔随机分为高脂对照组、锡原卟啉-9(SnPP-IX)组、普罗布考组、普罗布考+SnPP-IX组,每组15只,持续药物干预12周,24周末检测各组血脂,酶联免疫吸附(ELISA)法检测血清中氧化低密度脂蛋白、白介素-18、基质金属蛋白酶-9和超敏感C反应蛋白的水平;观测斑块的病理形态及组成;通过免疫组织化学法观察腹动脉组织中HO-1的表达,实时定量RT-PCR检测HO-1 mRNA的表达,酶法检测HO-1活性的变化。结果与对照组相比,普罗布考组斑块内HO-1的表达及活性显著增加,主动脉斑块面积、内-中膜厚度显著减小,斑块纤维帽厚度增加,免疫组化检测斑块内巨噬细胞浸润减少,血清中氧化低密度脂蛋白及炎症因子的水平降低(P均<0.01)。使用锡原卟啉-9抑制HO-1的产生及活性,促进了斑块的进展,增加了血浆中氧化及炎症因子的水平(P均<0.01)。普罗布考干预的同时抑制HO-1的活性,显著减弱了普罗布考的抗动脉粥硬化作用(P均<0.01)。结论普罗布考通过诱导HO-1产生发挥其抗炎、抗氧化作用,从而抑制动脉粥样硬化进展,增加斑块的稳定性。HO-1可能是普罗布考抗动脉粥样硬化的作用靶点。

Probucol protects against atherosclerosis through induction of heme oxygenase-1

Objective The heme oxygenase-1(HO-1) system of heme catabolism has been implicated in protection against atherosclerotic vascular diseases.This study was aimed to test the hypothesis that probucol could inhibit the progression and destabilization of plaques by induction of HO-1.Methods Atherosclerotic plaques were induced in aortas of 60 male New Zealand white rabbits by an atherogenic diet for 12 weeks after endothelial injury.Rabbits were then randomly divided into 4 groups which received no treatment,probucol,Sn protoporphyrin IX(SnPP IX),or probucol plus SnPP IX for 12 weeks.Serological,pathological,immunohistochemical and gene expression studies were performed at the end of the 24th week.Results Probucol significantly induced HO-1 mRNA,protein,and enzyme activity in atherosclerotic plaques.This induction was correlated with a reduction in the progression of plaque size.Furthermore,this induction resulted in features of plaque stability such as increasing fibrous cap thickness and less macrophage infiltration.Moreover,the serum levels of oxidized low density lipoprotein and pro-inflammatory factors,including matrix metalloproteinase-9,interleukin-18 and high sensitive C-reactive protein were remarkably reduced by probucol(P<0.01).In contrast,inhibition of HO-1 by SnPP IX not only augmented plaque progression and vulnerability but also raised the serum levels of the oxidized and pro-inflammatory factors(P<0.01).So it significantly reduced the effects of probucol(P<0.01).Conclusions Our results demonstrated that probucol treatment may inhibit atherosclerosis progression and promote plaque stability by induction of HO-1.HO-1 may be the target of probucol′s anti-atherosclerosis action.