Induction of ATF3 gene network by triglyceride-rich lipoprotein lipolysis products increases vascular apoptosis and inflammation.
Induction of ATF3 gene network by triglyceride-rich lipoprotein lipolysis products increases vascular apoptosis and inflammation.
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DOI：
10.1161/atvbaha.113.301375
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发表时间：
2013-09
期刊：
影响因子：
--
通讯作者：
Rutledge JC
中科院分区：
文献类型：
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作者：
Aung HH;Lame MW;Gohil K;An CI;Wilson DW;Rutledge JC
富含甘油三酯的脂蛋白（TGRL）升高会增加动脉粥样硬化性心血管疾病（ASCVD）的风险。我们的工作表明，高生理至病理生理浓度的 TGRL 脂解产物会导致内皮细胞损伤；然而，其机制仍有待界定。我们分析了暴露于 TGRL 脂解产物的动脉内皮细胞中的转录信号网络。当培养的人主动脉内皮细胞 (HAEC) 暴露于 TGRL 脂解产物时，激活转录因子 3 (ATF3) 被确定为主要反应基因。通过 qRT-PCR 和蛋白质印迹证实了 ATF3 mRNA 和蛋白质的诱导。免疫荧光分析表明，ATF3 在用脂解产物处理的细胞核中积累。 p-JNK 的核表达（先前被证明是 ATF3 信号级联的启动子）也得到了证实。 siRNA 介导的 ATF3 抑制可阻断脂解产物诱导的 E-选择素和 IL-8 转录，但不能阻断 IL-6 或 NFκB。 JNK 通路中的下游蛋白 c-Jun 被磷酸化，同时 NFκB 依赖性 JunB 的表达下调。此外，JNK siRNA 抑制 ATF3 和 p-c-Jun 蛋白表达，表明 JNK 是 ATF3 信号通路的上游。体内研究表明，将TGRL脂解产物输注至野生型小鼠体内可诱导颈动脉内皮细胞核ATF3的积累。 ATF3−/− 小鼠对 TGRL 脂解产物治疗引发的血管凋亡具有抵抗力。此外，与空腹单核细胞相比，从餐后人类分离的外周血单核细胞的 ATF3 表达增加。这项研究表明，TGRL 脂解产物激活 ATF3-JNK 转录因子网络并诱导内皮细胞炎症反应。
Elevation of triglyceride-rich lipoproteins (TGRL) contributes to the risk for atherosclerotic cardiovascular disease (ASCVD). Our work has shown that TGRL lipolysis products in high physiological to pathophysiological concentrations cause endothelial cell injury; however, the mechanisms remain to be delineated. We analyzed the transcriptional signaling networks in arterial endothelial cells exposed to TGRL lipolysis products. When human aortic endothelial cells (HAEC) in culture were exposed to TGRL lipolysis products, activating transcription factor 3 (ATF3) was identified as a principal response gene. Induction of ATF3 mRNA and protein was confirmed by qRT-PCR and western blot. Immunofluorescence analysis showed that ATF3 accumulated in the nuclei of cells treated with lipolysis products. Nuclear expression of p-JNK, previously shown to be an initiator of the ATF3 signaling cascade, also was demonstrated. siRNA-mediated inhibition of ATF3 blocked lipolysis products-induced transcription of E-selectin and IL-8, but not IL-6 or NFκB. c-Jun, a downstream protein in the JNK pathway was phosphorylated while expression of NFκB-dependant JunB was down-regulated. Additionally, JNK siRNA suppressed ATF3 and p-c-Jun protein expression suggesting that JNK is up-stream of the ATF3 signaling pathway. In vivo studies demonstrated that infusion of TGRL lipolysis products into wild type mice induced nuclear ATF3 accumulation in carotid artery endothelium. ATF3−/− mice were resistant to vascular apoptosis precipitated by treatment with TGRL lipolysis products. Also peripheral blood monocytes isolated from postprandial humans had increased ATF3 expression as compared to fasting monocytes. This study demonstrates that TGRL lipolysis products activate ATF3-JNK transcription factor networks and induce endothelial cells inflammatory response.