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A more recent version of this article appeared on May 1, 2006

Papers In Press, published online ahead of print February 5, 2006
J. Lipid Res., doi:10.1194/jlr.M500555-JLR200
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Submitted on December 22, 2005
Revised on February 3, 2006
Accepted on February 4, 2006

Specific monocyte adhesion to endothelial cells induced by oxidized phospholipids involves activation of cPLA2 and lipoxygenase

Joakim Huber, Alexander Fuernkranz, Valery N. Bochkov, Mary K. Patricia, Hans Lee, Catherine C. Hedrick, Judith A. Berliner, Bernd R. Binder, and Norbert Leitinger

Cardiovascular Research Center, Universitiy of Virginia, Charlottesville, VA 22908

Corresponding Author: nl2q{at}virginia.edu

Oxidized phospholipids stimulate endothelial cells to bind monocytes, but not neutrophils, an initiating event in atherogenesis. Here, we investigate intracellular signaling events induced by oxidized phospholipids in human umbilical vein endothelial cells (HUVEC) that lead to specific monocyte adhesion. In a static adhesion assay, oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (OxPAPC) and one of its components, 1-palmitoyl-2-oxovaleroyl-sn-glycero-3-phosphorylcholine (POVPC), stimulated HUVEC to bind U937 cells and human peripheral blood monocytes, but not HL-60 cells or blood neutrophils. Monocyte adhesion was dependent on protein kinases A and C, ERK 1/2 and p38 mitogen activated protein kinases (MAPK), and cytosolic phospholipase A2 (cPLA2). Inhibition of 12-lipoxygenase, but not cyclooxygenases, blocked monocyte adhesion, and addition of 12-HETE mimicked the effects of oxidiezed phospholipids. PPARalpha was excluded as a possible target for 12-HETE, since monocyte adhesion was still induced in endothelial cells from PPARalpha null mice. Taken together, our results suggest that oxidized phospholipids stimulate HUVEC to specifically bind monocytes involving MAPK pathways, which lead to the activation of cPLA2 and 12-lipoxygenase. Further analysis of signaling pathways induced by oxidized phospholipids that lead to specific monocyte adhesion should ultimately lead to the development of novel therapeutic approaches against chronic inflammatory diseases.


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