SIRT1抑制ox-LDL诱导血管平滑肌细胞泡沫化的机制研究

A Study on the Mechanism of SIRT1 Inhibiting Foaming of Vascular Smooth Muscle Cells induced by ox-LDL

目的探讨沉默信息调节因子1(SIRT1)抑制氧化型低密度脂蛋白(ox-LDL)诱导的血管平滑肌细胞(VSMC)泡沫化的作用机制。方法取小鼠胸主动脉组织采用贴块法培养原代VSMC;ox-LDL诱导VSMC形成泡沫细胞;油红染色观察细胞内脂质聚集情况;Western blot法检测细胞中SIRT1、三磷酸腺苷结合盒转运子A1(ABCA1)及肝X受体α(LXRα)的表达情况。结果ox-LDL可诱导VSMC内脂质聚集,形成泡沫细胞,同时下调VSMC中SIRT1的表达;SIRT1激动剂(SRT1720,SRT)显著上调细胞中SIRT1的表达,减轻细胞内脂质沉积,SIRT1抑制剂(Nic)抑制了SRT的作用;ox-LDL抑制VSMC中ABCA1的表达,SRT显著上调细胞中ABCA1的表达,Nic阻断其作用,抑制ABCA1表达;ox-LDL下调VSMC中LXRα表达,SRT上调细胞中LXRα表达,Nic逆转了SRT的作用,使VSMC中LXRα表达显著下调。LXRα激动剂GW3965显著上调VSMC中ABCA1的表达并且减轻了ox-LDL诱导的细胞内脂质聚集,而LXRα抑制剂GGPP则显著抑制ABCA1的表达,明显加强VSMC中脂质聚集。结论SIRT1通过上调VSMC中LXRα的表达、促进ABCA1的表达,从而抑制ox-LDL诱导的VSMC泡沫化。

Objective To investigate the mechanism of silent mating type information regulation 2 homolog-1(SIRT1)inhibiting foaming of vascular smooth muscle cell(VSMC)induced by oxidized low-density lipoprotein(ox-LDL).Methods Primary VSMCs isolated from thoracic aorta tissues of mice were cultured by patching method.Foam cells were derived by ox-LDL inducing VSMCs.The condition of intracellular lipid accumulation in foam cells was observed by Oil Red O staining.Expressions of SIRT1,adenosine triphosphate binding cassette transporter A1(ABCA1)and liver X receptorα(LXRα)in cells were detected by Western blot method.Results The ox-LDL could induce lipid accumulation in VSMCs to form foam cells,and down-regulate SIRT1 expression in VSMCs.SIRT1 agonist(SRT1720,SRT)significantly up-regulated SIRT1 expression and reduced intracellular lipid deposition.SIRT1 antagonist nicotinamide(Nic)inhibited the effect of SRT.The ox-LDL inhibited ABCA1 expression in VSMCs.SRT significantly up-regulated ABCA1 expression in cells,and Nic blocked its effect and inhibited ABCA1 expression.The ox-LDL down-regulated LXRαexpression in VSMCs,while SRT up-regulated LXRαexpression in cells;Nic reversed the effect of SRT and significantly down-regulated LXRαexpression in VSMCs.LXRαagonist GW3965 significantly up-regulated ABCA1 expression in VSMCs and reduced the intracellular lipid aggregation induced by ox-LDL,while LXRαinhibitor GGPP significantly inhibited ABCA1 expression and significantly enhanced the lipid aggregation in VSMCs.Conclusion SIRT1 may inhibit formation of foam cells induced by ox-LDL in VSMCs by up-regulating LXRαexpression in VSMCs and promoting ABCA1 expression.