出版社：American Society for Biochemistry and Molecular Biology
摘要：Oxidized phospholipids stimulate endothelial cells to bind monocytes,but not neutrophils, an initiating event in atherogenesis. Here,we investigate intracellular signaling events induced by oxidizedphospholipids in human umbilical vein endothelial cells (HUVECs)that lead to specific monocyte adhesion. In a static adhesionassay, oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholineand one of its components, 1-palmitoyl-2-oxovaleroyl-sn-glycero-3-phosphorylcholine,stimulated HUVECs to bind U937 cells and human peripheral bloodmonocytes but not HL-60 cells or blood neutrophils. Monocyteadhesion was dependent on protein kinases A and C, extracellularsignal-regulated kinase 1/2, p38 mitogen activated protein kinases(MAPKs), and cytosolic phospholipase A2 (cPLA2). Inhibitionof 12-lipoxygenase (12-LOX), but not cyclooxygenases, blockedmonocyte adhesion, and addition of 12-hydroxyeicosatetraenoicacid (12-HETE) mimicked the effects of oxidized phospholipids.Peroxisome proliferator-activated receptor (PPAR) was excludedas a possible target for 12-HETE, because monocyte adhesionwas still induced in endothelial cells from PPAR null mice.Together, our results suggest that oxidized phospholipids stimulateHUVECs to specifically bind monocytes involving MAPK pathways,which lead to the activation of cPLA2 and 12-LOX. Further analysisof signaling pathways induced by oxidized phospholipids thatlead to specific monocyte adhesion should ultimately lead tothe development of novel therapeutic approaches against chronicinflammatory diseases.Supplementary key words atherosclerosis • endothelial cells • 12-lipoxygenase • cytosolic phospholipase A2Abbreviations: 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
(PPAR
B, nuclear factor-
