阿托伐他汀下调内皮细胞Toll样受体4及其下游分子的表达  

Atorvastatin Decreased Toll-Like Receptor 4 Expression and Downstream Signals in Human Endothelial Cells

作　　者：王虹艳[1] 曲鹏[1] 姜华[1] 

机构地区：[1]大连医科大学附属第二医院心血管内科,辽宁大连116027

出　　处：《中华高血压杂志》2009年第6期524-528,共5页Chinese Journal of Hypertension

基　　金：国家自然科学基金资助项目(编号:30371568)

摘　　要：背景他汀类药物有独立于调脂作用之外的抗炎作用。近年研究表明Toll-样受体4(TLR4)参与了动脉粥样硬化的形成和发展。目的观察阿托伐他汀对脂多糖(LPS)诱导的内皮细胞TLR4及其下游分子表达的影响,以探讨他汀类药物抗炎作用的分子机制。方法采用阿托伐他汀(1及10μmol/L)或核转录因子(NF)κB抑制剂咖啡酸苯乙酯(CAPE)预孵育人脐静脉内皮细胞(HUVEC)30min后,应用LPS(1mg/L)作用24h。逆转录聚合酶链反应(RT-PCR)方法检测TLR4、细胞间黏附分子1(ICAM-1)和E选择素mRNA表达水平;采用流式细胞术检测TLR4蛋白表达水平;采用蛋白质印迹技术检测核蛋白NF-κBp65表达的变化。结果与LPS组比较,阿托伐他汀1μmol/L组减轻LPS介导的TLR4表达增加[TLR4mRNA:(1.24±0.21)比LPS组(1.82±0.27),P<0.05;TLR4阳性细胞数(50.1±4.7)%比LPS组(69.5±7.8)%,P<0.05],阿托伐他汀减轻LPS介导的ICAM-1和E选择素的表达增加。阿托伐他汀抑制LPS介导的NF-κBp65活化(50.4±10.1比LPS组72.3±12.5,P<0.05),10μmol/L阿托伐他汀较1μmol/L作用更明显;CAPE(20mg/L)也明显抑制了LPS介导的TLR4及ICAM-1和E选择素表达上调。结论阿托伐他汀抑制TLR4/NF-κB及其下游分子表达是他汀类药物抗炎作用机制之一。Background The impact of statins on inflammation are independent of cholesterol-lowering effect. Recent studies showed that Toll like receptor 4 （TLR4）, a mediator of innate immune responses, is involved in the initiation and progression of atherosclerosis. Objective To investigate the effects of atorvastatin on LPS-induced TLR4 expression and downstream signals and to explore the molecular mechanisms of anti-inflammation by statins. Methods Human umbilical vein endothelial cells （HUVEC） were pretreated with atorvastatin （1 or 10 μmol/L） or NF-κB inhibitor CAPE for 30 min, then incubated by purified LPS for 24 hours. TLR4, ICAM-1 and E-selectin mRNA were measured by RT-PCR; the percentage of TLR4 positive cells were detected by flow cytometry. The activation of NF-κB（p65） were detected by Western blot. Results Atorvastatin（1-10 μmol/L）prevented LPS-induced increases in TLR4, ICAM-1 and E-selectin expression [TLR4 mRNA （1.24±0.21） vs LPS （1.82±0.27）, P〈0.05 ;percentage of TLR4 positive cell （50.1±4.7）% vs LPS （69.5±7.8）%, P〈0. 053. Atorvastatin also attenuated LPS-induced ICAM-1]. E-selectin and NF-κB activation（50.4± 10.1 vs LPS 72.3 ±12.5, P〉0.05）. NF-κB inhibitor CAPE suppressed LPS-induced above-mentioned effects similarly. Conclusion Decreases in TLR4 and its downstream signals might be one of mechanisms goverfling anti-inflammation by statins.

关 键 词：人脐静脉内皮细胞 阿托伐他汀 脂多糖 TOLL样受体4 核转录因子ΚB 细胞间黏附分子1 E选择素 

分 类 号：R543[医药卫生—心血管疾病]