Mitogen-activated protein kinase phosphatase 1 activity is necessary for oxidized phospholipids to induce monocyte chemotactic activity in human aortic endothelial cells

Entrapment and oxidation of low density lipoproteins (LDL) in the sub-endot helial space is a key process in the initiation of atherosclerotic lesion d evelopment. Functional changes induced by oxidized lipids in endothelial ce lls are early events in the pathogenesis of atherosclerosis, Oxidized-L-alp ha -1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (ox-PAPC), a maj or component of minimally modified/oxidized-LDL (MM-LDL) mimics the biologi cal activities assigned to MP-LDL both in vitro in a co-culture model as we ll as in vivo in mice. We hypothesized that ox-PAPC initiates gene expressi on changes in endothelial cells that result in enhanced endothelial/monocyt e interactions. To analyze the gene expression changes that oxidized lipids induce in endothelial cells, we used a suppression subtractive hybridizati on procedure to compare mRNA from PAPC-treated human aortic endothelial cel ls (HAEC) with that of ox-PAPC-treated cells. We report here the identifica tion of a gene, mitogen-activated protein kinase phosphatase 1 (MKP-1), tha t is rapidly and transiently induced in ox-PAPC-treated HAEC. Inhibition of MKP-1 using either the phosphatase inhibitor sodium orthovanadate or antis ense oligonucleotides prevents the accumulation of monocyte chemotactic act ivity in ox-PAPC-treated HAEC supernatants, Furthermore, we show that decre ased monocyte chemotactic activity in HAEC treated with sodium orthovanadat e or MKP-1 antisense oligonucleotides is due to decreased MCP-1 protein. Ou r results implicate a direct role for MKP-1 in ox-PAPC-induced signaling pa thways that result in the production of MCP-1 protein by ox-PAPC-treated HA EC.