Circulating Polymorphonuclear Leukocytes Cell as a Risk Factor for Endothelial injury in Humans

动脉粥样硬化被认为是一种全身性炎症过程。尽管在高胆固醇血症模型中，降脂治疗部分是通过HSP90介导的内皮型一氧化氮合酶的磷酸化来恢复内皮功能，但确切的机制仍有待阐明。在目前的体内和体外研究中，我们调查了多形核白细胞(PMN)和内皮功能之间的可能联系以及降脂治疗的效果。在研究的第一部分，没有其他冠状动脉危险因素的高胆固醇血症受试者被随机分为氟伐他汀或可伐他汀，采用交叉设计。服用3个月的氟伐他汀或考司他特以类似的方式降低低密度脂蛋白(p=0.0001)。只有接受氟伐他汀治疗的受试者才能恢复内皮功能(p=0.0001)，这是通过血流介导的臂动脉扩张来评估的。同样，氟伐他汀改善了低密度脂蛋白对氧化的敏感性(p=0.007)，并减少了PMN释放的超氧化物(p=.001)，而考司他汀对脂质过氧化或炎性细胞活动都没有影响。在体外研究的第二部分，Western印迹分析显示，暴露于高胆固醇血症患者的PMN会损害培养的内皮细胞中一氧化氮合酶(ENOS)的磷酸化，而慢性氟伐他汀治疗会使eNOS的磷酸化恢复正常(p=.01)。因此，他汀类药物通过其抗炎特性改善内皮功能，而不依赖于降低低密度脂蛋白。我们的结果提出了一个新的概念，即循环中的PMN释放大量的超氧化物，可能直接攻击内皮细胞，在动脉粥样硬化的发病机制中发挥关键作用。

Atherosclerosis is considered as a systemic inflammatory process. Although lipid lowering therapies restore endothelial function partly through hsp90-mediated phosphorylation of endothelial nitric synthase in hypercholesterolemic models, precise mechanisms remain to be elucidated. In the present in vivo and ex vivo studies, we investigated a possible link between polymorphonuclear leukocytes (PMN) and endothelial function and the effects of lipid lowering therapies. In the first part of study, hypercholesterolemic subjects without other coronary risk factors were randomized to have fluvastatin or colestimide in a crossover design. Three months administration of fluvastatin or colestimide lowered LDL in a similar manner (p=.0001 for both). Endothelial function, estimated by flow-mediated vasodilation of the brachial artery, was restored only in fluvastatin-treated subjects (p=.0001). Similarly, fluvastatin improved the susceptibility of LDL to oxidation (p=.007) and attenuated superoxide release from PMN (p=.001), whereas colestimide had no effects on either lipid peroxidation or inflammatory cell activity. In the second part of ex vivo study, western blot analysis revealed that the exposure of PMN obtained from hypercholesterolemic subjects impaired the phosphorylation of nitric oxide synthase (eNOS) in cultured endothelial cells, whereas chronic fluvastatin treatment normalized eNOS phospholylation (p=.01). Thus, statin improved endothelial function by its anti-inflammatory properties, independent of LDL reduction. Our results raise a novel concept that circulating PMN, which burst a large amount of superoxide, may directly attack endothelia and play a pivotal role in the pathogenesis of atherosclerosis.