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抗氧化剂通过亚铁血红素氧化酶1途径预防动脉粥样硬化的作用不依赖于自由基的清除

摘要：
    氧化应激与动脉粥样硬化有关，然而大量临床研究表明抗氧化剂，特别是维生素E并不能预防动脉粥样硬化性疾病。但普罗布考是一个例外，它能够延缓冠状动脉血管成形术后再狭窄和颈动脉内粥样硬化的进展。因为在体外普罗布考的细胞保护作用不依赖于抑制脂质氧化，因此该研究从体内研究了普罗布考的作用机理。研究采用了三种血管病模型：1.敲除载脂蛋白E基因的小鼠作为动脉粥样硬化模型；2. 经球囊损伤主动脉的兔作为再狭窄模型；3.损伤颈动脉的Zucker肥胖大鼠作为2型糖尿病模型。研究者意外的发现普罗布考中缺乏苯酚基团，而苯酚基团中的硫原子必需得到保护。普罗布考及它的含硫代谢物能够通过抑制巨噬细胞的聚集，刺激血管内膜再内皮化和抑制血管平滑肌细胞增生得到保护，而含自由硫原子的苯酚异构物得不到保护。诱导出的亚铁血红素氧化酶1（HO-1）能够介导这个过程，但维生素E不具有这种特性。证明HO-1是普罗布考在分子水平的作用靶点。这些研究结果表明促进动脉粥样硬化发展最重要的是双电子而不是单电子的氧化剂，并指出了新的治疗动脉粥样硬化性疾病前驱化合物的研究方向。


Antioxidants protect from atherosclerosis by a heme oxygenase-1 pathway that is independent of free radical scavenging

        The First three authors: Ben J. Wu, Krishna Kathir, Paul K. Witting
   Corresponding and Adress: K. Kathir, Vascular Biology Group, ANZAC Research Institute, Concord Hospital, Australia.

Abstract:
Oxidative stress is implicated in atherogenesis, yet most clinical trials with antioxidants, particularly vitamin E, have failed to protect against atherosclerotic diseases. A striking exception is probucol, which retards atherosclerosis in carotid arteries and restenosis of coronary arteries after angioplasty. Because probucol has in vitro cellular-protective effects independent of inhibiting lipid oxidation, we investigated the mode of action of probucol in vivo. We used three models of vascular disease: apolipoprotein E–defi cient mice, a model of atherosclerosis; rabbit aortic balloon injury, a model of restenosis; and carotid injury in obese Zucker rats, a model of type 2 diabetes. Unexpectedly, we observed that the phenol moieties of probucol were insufficient, whereas its sulphur atoms were required for protection. Probucol and its sulphur-containing metabolite, but not a sulphur-free phenolic analogue, protected via cell-specifi c effects on inhibiting macrophage accumulation, stimulating reendothelialization, and inhibiting vascular smooth muscle cell proliferation. These processes were mediated via induction of heme oxygenase-1 (HO-1), an activity not shared by vitamin E. Our findings identify HO-1 as the molecular target of probucol. They indicate 2-electron rather than radical (1-electron) oxidants as important contributors to atherogenesis, and point to novel lead compounds for therapeutic intervention against atherosclerotic diseases.

摘自：The Journal of Experimental Medicine. 2006; 203(4): 1117-1127
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