沉默信息调节因子1-肝X受体/核因子-κB信号通路在促使动脉粥样硬化斑块消退中的作用

Effect of silent information regulator 1-liver X receptor/nuclear factor kappa B signaling pathways on promoting atherosclerotic plaque regression

目的研究沉默信息调节因子1(silent information regulator 1,SIRT1)与泡沫细胞移出动脉粥样硬化斑块相关调控通路肝X受体(liver X receptor,LXR)-趋化因子受体7(chemokine receptor-7,CCR7)和促炎症信号核因子-κB(nuclear factor kappa B,NF-κB)的相关性。方法体外培养人单核细胞株U937细胞,构建泡沫细胞模型;分别用SIRT1激动剂SRT1720和RNA干扰等方法使SIRT1高表达或抑制其表达,观察SIRT1和其下游靶分子LXR、CCR7以及促炎因子NF-κB、肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)的表达变化。结果在泡沫细胞模型中,SRT1720使SIRT1蛋白表达水平升高,LXR和其靶分子CCR7蛋白水平无显著变化,而NF-κB以及其靶分子TNF-α蛋白表达水平显著下降。在加入SRT1720的基础上再用RNA干扰抑制SIRT1的表达,结果表明RNA干扰使SIRT1的表达水平显著下降,LXR和其靶分子CCR7表达也随之下降;与此同时,NF-κB及其下游靶基因TNF-α表达水平显著升高。结论在泡沫细胞中SIRT1可能是LXR-CCR7以及NF-κB信号通路的上游,并且有可能通过上调LXR-CCR7信号通路,抑制NF-κB炎症信号来参与调节泡沫细胞从动脉粥样硬化斑块中移出。

Objectives To examine and indentify the association of silent information regulator 1（SIRT1） with liver X receptor（LXR）- chemokine receptor-7（CCR7） signaling involved in the egress of foam cells from atherosclerotic plaques and nuclear factor kappa B（NF-κB）-mediated pro-inflammatory pathway. Methods A model of monocyte-derived foam cells was established using human monocytic cell line U937 in vitro. SIRT1 activator SRT1720 and RNA interference were used to activate or suppress the expression of SIRT1. Protein expressions of SIRT1,LXR,CCR7,NF-κB and tumor necrosis factor-α（TNF-α） were examined by Western blot. Results After a 24-h stimulation by SRT1720,expression of SIRT1 was significantly up-regulated in foam cell. However,expressions of LXR and its target gene CCR7 did not change,whereas,NF-κB and its target gene TNF-α decreased significantly. When SIRT1 expression was obviously suppressed by RNA interference,expressions of LXR and CCR7 also significantly decreased,whereas NF-κB and TNF-αsignificantly increased. Conclusions Our present study indicates that SIRT1 is probably the upstream of LXR-CCR7 and NF-κB signaling pathways in foam cell,which suggests that SIRT1 may positively regulate monocyte-derived foam cell migration through upregulating LXR-CCR7 pathway and inhibiting NF- κB-mediated inflammatory signaling.