The impairment of endothelium-dependent arterial relaxation by 7-ketocholesterol is associated with an early activation of protein kinase C
The impairment of endothelium-dependent arterial relaxation by 7-ketocholesterol is associated with an early activation of protein kinase C
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DOI：
10.1038/sj.bjp.0704920
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发表时间：
2002-11-01
影响因子：
7.3
通讯作者：
Lagrost, L
中科院分区：
文献类型：
--
作者：
Deckert, V;Duverneuil, L;Lagrost, L
1在氧化低密度脂蛋白的组分中，7位氧化的胆固醇衍生物通过减少主要内皮源性舒张因子一氧化氮（NO）的释放来抑制内皮依赖性动脉舒张。本研究的目的是为7-酮基胆固醇阻断内皮依赖性动脉舒张的分子机制带来新的见解。2超氧化物歧化酶不能阻止7-酮基胆固醇对内皮依赖性舒张的抑制作用，并且无论超氧化物歧化酶是否与聚乙二醇结合，都进行了一致的观察。此外，无论是谷胱甘肽补充剂，还是oxypurinol，即黄嘌呤氧化酶抑制剂，都不能逆转7-酮胆固醇的作用，表明NO不会被超氧阴离子灭活。3也可以排除钙依赖性NO合酶活性的直接改变，因为无论用7-羟色胺处理或不处理动脉环，都观察到钙离子载体A23187具有相同的舒张作用。尽管上述观察结果支持7-酮基胆固醇的早期抑制作用，但可以放弃对一种给定的膜受体亚型的特异性阻断，并且当毒蕈碱或嘌呤能受体受到刺激时观察到类似的抑制。白屈菜红碱对蛋白激酶C活性的阻断是防止7-酮基胆固醇对兔主动脉环内皮依赖性舒张作用的唯一相关工具。此外，对培养的牛主动脉内皮细胞的补充研究直接支持7-酮基胆固醇激活PKC的能力。6总之，存在于人类高胆固醇血症血浆、动脉粥样硬化动脉和许多加工食品中的7-酮基胆固醇可以通过其激活PKC的能力阻断血管内皮细胞释放NO。
1 Among components of oxidized low density lipoproteins, cholesterol derivatives oxidized in position 7 inhibit endothelium-dependent arterial relaxation by decreasing the release of the main endothelium-derived relaxing factor, nitric oxide (NO). The aim of the present study was to bring new insights into the molecular mechanism by which 7-ketocholesterol can block the endothelium-dependent arterial relaxation.2 Superoxide dismutase did not prevent the inhibitory effect of 7-ketocholesterol on endothelium-dependent relaxation, and consistent observations were made whether superoxide dismutase was conjugated or not to polyethylene glycol. In addition, neither glutathione supplementation, nor oxypurinol, i.e. a xanthine oxidase inhibitor could reverse the effect of 7-ketocholesterol, indicating that NO was not inactivated by superoxide anion.3 A direct alteration of the activity of the calcium-dependent NO synthase could also be ruled out, since identical relaxing effects of the calcium ionophore A23187 were observed whether arterial rings were treated or not with 7-ketocholesterol.4 Whereas the above observations come in support of an early, inhibitory action of 7-ketocholesterol, the specific blockade of one given subtype of membrane receptors could be discarded, and similar inhibitions were observed when either muscarinic or purinergic receptors were stimulated.5 Finally, the blockade of protein kinase C activity by chelerythrine arose as the sole relevant tool in preventing the effect of 7-ketocholesterol on the endothelium-dependent relaxation of rabbit aortic rings. In addition, complementary studies on cultured bovine aortic endothelial cells came in direct support of the ability of 7-ketocholesterol to activate PKC.6 In conclusion, 7-ketocholesterol that is present in human hypercholesterolaemic plasma, in atherosclerotic arteries, and in many processed foods can block the release of NO by vascular endothelial cells through its ability to activate PKC.