Abstract
Entrapment and oxidation of low density lipoproteins (LDL) in the sub-endothelial space is a key process in the initiation of atherosclerotic lesion development. Functional changes induced by oxidized lipids in endothelial cells are early events in the pathogenesis of atherosclerosis. Oxidized-l-alpha-1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (ox-PAPC), a major component of minimally modified/oxidized-LDL (MM-LDL) mimics the biological activities assigned to MM-LDL both in vitro in a co-culture model as well as in vivo in mice. We hypothesized that ox-PAPC initiates gene expression changes in endothelial cells that result in enhanced endothelial/monocyte interactions. To analyze the gene expression changes that oxidized lipids induce in endothelial cells, we used a suppression subtractive hybridization procedure to compare mRNA from PAPC-treated human aortic endothelial cells (HAEC) with that of ox-PAPC-treated cells. We report here the identification of a gene, mitogen-activated protein kinase phosphatase 1 (MKP-1), that is rapidly and transiently induced in ox-PAPC-treated HAEC. Inhibition of MKP-1 using either the phosphatase inhibitor sodium orthovanadate or antisense oligonucleotides prevents the accumulation of monocyte chemotactic activity in ox-PAPC-treated HAEC supernatants. Furthermore, we show that decreased monocyte chemotactic activity in HAEC treated with sodium orthovanadate or MKP-1 antisense oligonucleotides is due to decreased MCP-1 protein. Our results implicate a direct role for MKP-1 in ox-PAPC-induced signaling pathways that result in the production of MCP-1 protein by ox-PAPC-treated HAEC.
Highlights
In the sub-endothelial space and the subsequent interactions between endothelial cells and monocytes is a key process in the initiation of atherosclerotic lesion development [1, 2]
We show that decreased monocyte chemotactic activity in human aortic endothelial cells (HAEC) treated with sodium orthovanadate or mitogen-activated protein kinase phosphatase 1 (MKP-1) antisense oligonucleotides is due to decreased monocyte chemoattractant protein 1 (MCP-1) protein
Ox-PAPC Induces the Expression of MKP-1 in HAEC—To identify genes that are induced by ox-PAPC in HAEC, mRNA pooled from HAEC treated with 50 g/ml of ox-PAPC for 1, 2, and 4 h was subtracted from mRNA pooled from HAEC treated with 50 g/ml PAPC for 1, 2, and 4 h using the suppression subtractive hybridization technique [27]
Summary
In the sub-endothelial space and the subsequent interactions between endothelial cells and monocytes is a key process in the initiation of atherosclerotic lesion development [1, 2]. Inhibition of MKP-1 using either the phosphatase inhibitor sodium orthovanadate or antisense oligonucleotides prevents the accumulation of monocyte chemotactic activity in ox-PAPC-treated HAEC supernatants. We show that decreased monocyte chemotactic activity in HAEC treated with sodium orthovanadate or MKP-1 antisense oligonucleotides is due to decreased MCP-1 protein.
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