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A more recent version of this article appeared on March 1, 2008

Papers In Press, published online ahead of print December 10, 2007
J. Lipid Res., doi:10.1194/jlr.M700264-JLR200
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Submitted on June 11, 2007
Revised on December 7, 2007
Accepted on December 10, 2007

Protein targets of oxidized phospholipids in endothelial cells

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

Medicine/Cardiology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095

Corresponding Author: 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 low-density lipoproteins (Ox-LDL) and stimulate human aortic endothelial cells (HAEC) to produce inflammatory cytokines, leukocyte chemoattractants, and coagulation factors. This regulation is thought to be a receptor-mediated process where oxidized phospholipids activate specific receptors on HAEC 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 IL-8 protein synthesis and stimulated IL-8, LDL-R, HO-1, and ATF-3 mRNA expression in HAEC. After treatment of HAEC 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. Separation of individual oxidized species of Ox-PAPE-N-Biotin by semi-preparative HPLC, followed by incubation with HAEC, suggested that different lipids may recognize different endothelial cell proteins. Fluorescence and confocal microscopy of HAEC treated with Ox-PAPE-N-Biotin and probed with FITC-conjugated avidin showed a peri-nuclear localization of biotin-labeled proteins that co-localized with a Golgi stain. This work suggests that oxidized phospholipids, such as those found in Ox-LDL, apoptotic cells, and atherosclerotic lesions form tight interactions with specific endothelial cell proteins, which may be responsible for the inflammatory response. Identification of the proteins to which these lipids interact may provide therapeutic targets to modulate inflammation and atherosclerosis.


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