Ozer N K, Azzi A
Department of Biochemistry, Faculty of Medicine, Marmara University, 81326 Haydarpasa, Istanbul, Turkey.
Toxicology. 2000 Aug 7;148(2-3):179-85. doi: 10.1016/s0300-483x(00)00209-2.
The development of atherosclerosis is a multifactorial process in which both elevated plasma cholesterol levels and proliferation of smooth muscle cells play a central role. Numerous studies have suggested the involvement of oxidative processes in the pathogenesis of atherosclerosis and especially of oxidised low density lipoproteins. Some epidemiological studies have shown an association between high dietary intake or high serum concentrations of vitamin E and lower rates of ischemic heart disease. Recently, the Cambridge Heart Antioxidant Study (CHAOS) reported strong protection by high vitamin E doses against the risk of fatal and non fatal myocardial infarction. Here we have shown that incubation of vascular smooth muscle cells in the presence of alpha-tocopherol resulted in inhibition of cell proliferation and protein kinase C activity. Since beta-tocopherol and probucol are not inhibitory, the effect of alpha-tocopherol is considered due to a non-oxidant mechanism. In order to understand the protective role of alpha-tocopherol against atherosclerosis in vivo the following rabbit studies were carried out. Atherosclerosis was induced by a vitamin E poor diet containing 2% cholesterol in a group of rabbit. The other groups had 2% cholesterol in the diet plus 50 mg/kg vitamin E i.m. or 1% probucol or 50 mg/kg vitamin E plus 1% probucol. After 4 weeks, aortas were removed and analysed by microscopy for atherosclerotic lesions. Samples of the media were analysed for protein kinase C activity. The aortas of cholesterol-fed rabbits showed typical atherosclerotic lesions, detected by microscopic examination, their media smooth muscle cells exhibited an increase in protein kinase C activity. Vitamin E fully prevented cholesterol induced atherosclerotic lesions and the induction of protein kinase C activity while probucol was not effective. These results show that the protective effect of vitamin E against hypercholesterolemic atherosclerosis is not produced by an other antioxidant such as probucol and, therefore, may not be linked to the antioxidant properties of this vitamin. The effects observed at the level of smooth muscle cells in vitro and ex-vivo suggests an involvement of signal transduction events in the protective effect of vitamin E against atherosclerosis.
动脉粥样硬化的发展是一个多因素过程，其中血浆胆固醇水平升高和平滑肌细胞增殖都起着核心作用。大量研究表明氧化过程参与动脉粥样硬化的发病机制，尤其是氧化型低密度脂蛋白。一些流行病学研究显示，高膳食摄入或高血清浓度的维生素E与较低的缺血性心脏病发病率之间存在关联。最近，剑桥心脏抗氧化研究（CHAOS）报告称，高剂量维生素E对致命和非致命心肌梗死风险有强大的保护作用。我们在此表明，在α-生育酚存在的情况下培养血管平滑肌细胞会导致细胞增殖和蛋白激酶C活性受到抑制。由于β-生育酚和普罗布考没有抑制作用，α-生育酚的作用被认为是由于非氧化机制。为了了解α-生育酚在体内对动脉粥样硬化的保护作用，进行了以下兔子研究。一组兔子喂食含2%胆固醇的低维生素E饮食以诱导动脉粥样硬化。其他组的饮食中含有2%胆固醇，外加50mg/kg维生素E肌肉注射、1%普罗布考或50mg/kg维生素E加1%普罗布考。4周后，取出主动脉并通过显微镜分析动脉粥样硬化病变。分析中膜样本的蛋白激酶C活性。喂食胆固醇的兔子的主动脉显示出典型的动脉粥样硬化病变，通过显微镜检查检测到，它们的中膜平滑肌细胞蛋白激酶C活性增加。维生素E完全预防了胆固醇诱导的动脉粥样硬化病变和蛋白激酶C活性的诱导，而普罗布考则无效。这些结果表明，维生素E对高胆固醇血症性动脉粥样硬化的保护作用不是由普罗布考等其他抗氧化剂产生的，因此可能与该维生素的抗氧化特性无关。在体外和离体平滑肌细胞水平观察到的效应表明，信号转导事件参与了维生素E对动脉粥样硬化的保护作用。
