Published online before print August 24, 2006, doi: 10.1161/01.ATV.0000242903.41158.a1
© 2006 American Heart Association, Inc.
Vascular Biology |
The Unfolded Protein Response Is an Important Regulator of Inflammatory Genes in Endothelial Cells
From the Department of Medicine, Department of Microbiology, Immunology, and Molecular Genetics (P.S.G., M.J.C., J.P., A.J.L.), Department of Human Genetics (P.S.G., M.J.C., J.P., A.J.L.), and Department of Pathology (N.M.G., T.B.-O., J.A.B.), University of California, Los Angeles; and Bristol-Myers Squibb (W.-P.Y., A.H., A.T., T.G.K.), Pharmaceutical Research Institute, Princeton, NJ.
Correspondence to Aldons J. Lusis, UCLA Department of Medicine, Division of Cardiology, 470-123 CHS, Los Angeles, CA 90095-1679. E-mail jlusis{at}mednet.ucla.edu
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.
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. Our data suggest that the UPR pathway is a general mediator of vascular inflammation and EC dysfunction in atherosclerosis, and, likely, other inflammatory disorders.
Key Words: oxidized lipids • unfolded protein response • inflammation • endothelial cells • atherosclerosis
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