【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。更多还原

【Abstract】 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<0.05].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 governing anti-inflammation by statins.更多还原