XBP1型
未折叠蛋白反应
ATF4
内质网
趋化因子
细胞生物学
炎症
衣霉素
牛磺去氧胆酸
促炎细胞因子
白细胞介素8
罗亚
化学
癌症研究
生物
免疫学
信号转导
基因
生物化学
核糖核酸
RNA剪接
作者
Peter S. Gargalovic,Nima M. Gharavi,Michael J. Clark,Joanne Pagnon,Wen-Pin Yang,Aiqing He,Amy Truong,Tamar Baruch-Oren,Judith A. Berliner,Todd G. Kirchgessner,Aldons J. Lusis
标识
DOI:10.1161/01.atv.0000242903.41158.a1
摘要
Objective— Oxidized 1-palmitoyl-2-arachidonyl- sn -3-glycero-phosphorylcholine (oxPAPC) accumulates in atherosclerotic lesions and in vitro studies suggest that it mediates chronic inflammatory response in endothelial cells (ECs). The goal of our studies was to identify pathways mediating the induction of inflammatory genes by oxPAPC. Methods and Results— Using expression arrays, quantitative polymerase chain reaction (PCR), and immunoblotting we demonstrate that oxPAPC leads to endoplasmic reticulum stress and activation of the unfolded protein response (UPR) in human aortic ECs. Immunohistochemistry analysis of human atherosclerotic lesions indicated that UPR is induced in areas containing oxidized phospholipids. Using the UPR inducing agent tunicamycin and selective siRNA targeting of the ATF4 and XBP1 branches of the UPR, we demonstrate that these transcription factors are essential mediators of IL8, IL6, and MCP1 expression in human aortic ECs required for maximal inflammatory gene expression in the basal state and after oxPAPC treatment. We also identify a novel oxPAPC-induced chemokine, the CXC motif ligand 3 (CXCL3), and show that its expression requires XBP1. Conclusions— These data suggest that the UPR pathway is a general mediator of vascular inflammation and EC dysfunction in atherosclerosis, and, likely, other inflammatory disorders.
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