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Journal of Lipid Research, Vol. 47, 1054-1062, May 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

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

Joakim Huber^*, Alexander Fürnkranz^*, Valery N. Bochkov^*, Mary K. Patricia, Hans Lee, Catherine C. Hedrick, Judith A. Berliner, Bernd R. Binder^* and Norbert Leitinger^*,**,1

^* Department of Vascular Biology and Thrombosis Research, Medical University of Vienna, Vienna, Austria
Department of Medicine/Pathology, University of California Los Angeles, Los Angeles, CA
Department of Endocrinology and Metabolism
^** Department of Pharmacology and Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA

Published, JLR Papers in Press, February 5, 2006.

¹ To whom correspondence should be addressed. e-mail: 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 (HUVECs) that lead to specific monocyte adhesion. In a static adhesion assay, oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine and one of its components, 1-palmitoyl-2-oxovaleroyl-sn-glycero-3-phosphorylcholine, stimulated HUVECs 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, extracellular signal-regulated kinase 1/2, p38 mitogen activated protein kinases (MAPKs), and cytosolic phospholipase A₂ (cPLA₂). Inhibition of 12-lipoxygenase (12-LOX), but not cyclooxygenases, blocked monocyte adhesion, and addition of 12-hydroxyeicosatetraenoic acid (12-HETE) mimicked the effects of oxidized phospholipids. Peroxisome proliferator-activated receptor (PPAR) was excluded as a possible target for 12-HETE, because monocyte adhesion was still induced in endothelial cells from PPAR null mice. Together, our results suggest that oxidized phospholipids stimulate HUVECs to specifically bind monocytes involving MAPK pathways, which lead to the activation of cPLA₂ and 12-LOX. 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.

Supplementary key words atherosclerosis • endothelial cells • 12-lipoxygenase • cytosolic phospholipase A₂

Abbreviations: CDC, cinnamoyl-3,4-dihydroxy-a-cyanocinnamate; cPLA₂, cytosolic phospholipase A₂; CS-1, connecting segment-1; ERK 1/2, extracellular signal-regulated kinase 1/2; ETYA, 5,8,11,14-eicosatetraynoic acid; HAEC, human aortic endothelial cell; 12-HETE, 12-hydroxyeicosatetraenoic acid; HUVEC, human umbilical vein endothelial cell; ICAM-1, intercellular adhesion molecule-1; IL-8, interleukin 8; 12-LOX, 12-lipoxygenase; LPS, lipopolysaccharide; M199, medium 199; MAPK, mitogen-activated protein kinase; MCP-1, monocyte chemotactic protein-1; MEK, mitogen-activated ERK kinase; MM-LDL, minimally modified low density lipoprotein; NF-B, nuclear factor-B; OxPAPC, oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine; PKA, protein kinase A; PKC, protein kinase C; POVPC, 1-palmitoyl-2-oxovaleroyl-sn-glycero-3-phosphorylcholine; PPAR, peroxisome proliferator-activated receptor ; STAT3, signal transducer and activator of transcription 3; VCAM-1, vascular cell adhesion molecule-1

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