BACKGROUND: Increased vascular oxidative stress induced by hyperlipidemia may alter the phenotype of vascular smooth muscle (SM) cells and play a crucial role in the progression of atherosclerosis. To clarify the mechanisms underlying vascular dysfunction and oxidative stress in hypercholesterolemia, we compared the effects of antioxidant probucol with those of pravastatin on aortic stiffness, phenotypic modulation, oxidative stress, and NAD(P)H oxidase essential subunit p22(phox) expression in aortic medial SM cells of cholesterol-fed rabbits by using color image analysis of immunostained sections.

    METHODS AND RESULTS: Japanese white male rabbits were fed either normal chow or 1% cholesterol diet for 14 weeks. After the first 7 weeks, cholesterol-fed rabbits were further divided into 3 groups: those fed with cholesterol feed only and those additionally given pravastatin (10 mg/d) or probucol (1.3 g/d) for the last 7 weeks. Within 7 weeks of treatment, probucol improved aortic stiffness more effectively than did pravastatin, inhibiting phenotypic modulation by selectively upregulating contractile-type SM myosin heavy chain isoform SM2 and by reducing both p22(phox) and superoxide content in medial SM cells of cholesterol-fed rabbit aorta. No significant differences in cholesterol levels, superoxide content, and endothelial NO synthase levels in the intima, aortic morphology and fibrosis, and synthetic-type myosin heavy chain in medial SM cells were observed between the 2 drug-treated groups.

    CONCLUSIONS: These results suggest that oxidative stress and SM2 in medial SM cells might be important factors for vascular dysfunction, and strategies aimed at blocking NAD(P)H oxidase and upregulating SM2 may have therapeutic potential against the progression of atherosclerosis in hypercholesterolemia.

    背景：高血脂导致的血管氧化应激增加改变血管平滑肌细胞表型，在动脉粥样硬化进程中起着极为重要的作用。为阐明血管功能异常和高胆固醇血症中氧化应激的根本机制，本研究比较了普罗布考和普法他汀对胆固醇饲养家兔主主动脉硬化，主动脉内侧平滑肌细胞表型调节，氧化应激以及对NAD(P)H氧化酶亚组分p22(phox)表达的影作用。

    方法与结果：雄性日本白兔分别经正常饮食或1%胆固醇饮食饲养14周。饲养前七周后，胆固醇饮食饲养组分为3组：继续胆固醇饮食饲养组，添加普伐他汀（10mg/d）组和普罗布考组（1.3g/d）饲养后7周。与普法他汀相比，普罗布考治疗7周能够有效改善主动脉硬化，通过选择性上调收缩型平滑肌肌球蛋白重链SM2和降低主动脉内侧平滑肌细胞中的p22(phox)和过氧化物含量进而对表型调节产生抑制作用。两组间内膜胆固醇水平，过氧化物含量和内皮NO合成酶水平，以及主动脉形态及纤维化，内侧平滑肌细胞合成型肌球蛋白重链均无显著差异。

    结论：氧化应激和内侧平滑肌细胞中的SM2在血管功能失调中是非常重要的影响因素，阻断NAD(P)H氧化酶和上调SM2的治疗方案在延缓高胆固醇血症患者动脉粥样硬化进程中具有潜在疗效。