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

循环多形核白细胞是人类内皮损伤的危险因素

基本信息

批准号：
13670770
负责人：
MATSUOKA Hidehiro
金额：
$ 2.62万
依托单位：
KURUME UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

项目摘要

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.

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，降脂疗法部分通过hsp90介导的内皮型一氧化氮合酶磷酸化恢复内皮功能，但确切的机制仍有待阐明。在目前的体内和离体研究中，我们研究了多形核白细胞（PMN）与内皮功能和降脂治疗效果之间的可能联系。在研究的第一部分，无其他冠状动脉危险因素的高胆固醇血症受试者在交叉设计中随机分配氟伐他汀或colestimide。使用氟伐他汀或colestimide三个月降低LDL的方式相似（两者p= 0.0001）。通过肱动脉血流介导的血管舒张来评估的内皮功能仅在氟伐他汀治疗的受试者中得以恢复（p= 0.0001）。同样，氟伐他汀改善LDL对氧化的敏感性（p=.007），并减少PMN的超氧化物释放（p=.001），而colestimide对脂质过氧化或炎症细胞活性均无影响。在离体研究的第二部分，western blot分析显示，暴露于高胆固醇血症受试者的PMN会损害培养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使eNOS磷酸化正常化（p= 0.01）。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LDL。我们的研究结果提出了一个新的概念，即循环PMN可能会爆发大量的超氧化物，直接攻击内皮细胞，并在动脉粥样硬化的发病中发挥关键作用。