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Papers In Press, published online ahead of print March 1, 2008
J. Lipid Res., doi:10.1194/jlr.M700264-JLR200

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Journal of Lipid Research, Vol. 49, 510-520, March 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Protein targets of oxidized phospholipids in endothelial cells

B. Gabriel Gugiu^*, Kevin Mouillesseaux^*, Victoria Duong, Tabitha Herzog, Avetis Hekimian, Lukasz Koroniak, Thomas M. Vondriska^** and Andrew D. Watson^1,

^* Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095
Department of Medicine/Cardiology, University of California, Los Angeles, Los Angeles, CA 90095
Department of Chemistry/Biochemistry, University of California, Los Angeles, Los Angeles, CA 90095
^** Department of Anesthesiology/Medicine, University of California, Los Angeles, Los Angeles, CA 90095

The online version of this article (available at http://www.jlr.org) contains supplementary data in the form of sixteen figures and one table.

Published, JLR Papers in Press, December 10, 2007.

¹ To whom correspondence should be addressed. e-mail: awatson{at}mednet.ucla.edu

Oxidation products of 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphatidylcholine (Ox-PAPC) are found in atherosclerotic lesions, apoptotic cells, and oxidized LDL and stimulate human aortic endothelial cells (HAECs) to produce inflammatory cytokines, leukocyte chemoattractants, and coagulation factors. This regulation is thought to be a receptor-mediated process in which oxidized phospholipids activate specific receptors on HAECs to evoke an inflammatory response. To characterize the HAEC proteins with which oxidized phospholipids interact, a biotinylated PAPC analog, 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphatidyl-(N-biotinylethanolamine) (PAPE-N-biotin), was synthesized. Oxidation of PAPE-N-biotin in air generated a mixture of biotin-labeled oxidized lipids analogous to Ox-PAPC. Ox-PAPE-N-biotin, like Ox-PAPC, induced interleukin-8 (IL-8) protein synthesis and stimulated IL-8, low density lipoprotein receptor, heme oxygenase-1, and activating transcription factor-3 mRNA expression in HAECs. After treatment of HAECs with Ox-PAPE-N-biotin, the cellular proteins were isolated and separated by SDS-PAGE. Western analysis with streptavidin-HRP demonstrated at least 20 different biotinylated HAEC proteins to which the Ox-PAPE-N-biotin was associated, which were not detected with unoxidized PAPE-N-biotin treatment. This work suggests that oxidized phospholipids, such as those found in oxidized LDL, apoptotic cells, and atherosclerotic lesions, form tight interactions with specific endothelial cell proteins, which may be responsible for the inflammatory response. Identification of these putative oxidized phospholipid targets may reveal therapeutic targets to modulate inflammation and atherosclerosis.

Supplementary key words atherosclerosis • inflammation • lipid peroxidation • mass spectrometry • lipoproteins • interleukin-8 • monocyte chemoattractant protein-1 • biotinylation

Abbreviations: BODIPY, dipyromethene boron difluoride; CKAP4, cytoskeleton-associated protein-4; HAEC, human aortic endothelial cell; IL-8, interleukin-8; Ox-X, oxidation products of X; PAPC, 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphatidylcholine; PAPE, 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphatidylethanolamine; PAPE-N-biotin, 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphatidyl-(N-biotinylethanolamine); PEIPC, 1-palmitoyl-2-(5,6-epoxyisoprostane E₂)-sn-glycero-3-phosphatidylcholine; PEIPE-N-biotin, 1-palmitoyl-2-(5,6-epoxyisoprostane E₂)-sn-glycero-3-phosphatidyl-(N-biotinylethanolamine); PGPC, 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphatidylcholine; POVPC, 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphatidylcholine; PVDF, polyvinylidene difluoride; sulfo-NHS-biotin, biotin ester of N-hydroxysuccinimide sulfonate

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