Published online before print February 2, 2006, doi: 10.1161/01.RES.0000207394.39249.fc
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© 2006 American Heart Association, Inc.
Molecular Medicine |
Identification of Prostaglandin E2 Receptor Subtype 2 As a Receptor Activated by OxPAPC
From the Departments of Pathology (R.L., N.G., M.D., J.A.B.), Medicine (R.L., K.P.M., D.M., D.C., J.A.B.), Chemistry and Biochemistry (L.K.), University of California, Los Angeles.
Correspondence to Judith A Berliner, PhD, UCLA-Department of Medicine, 10833 Le Conte Ave, CHS 13-229, Los Angeles, CA 90095. E-mail jberliner{at}mednet.ucla.edu
Oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (OxPAPC), which has been shown to accumulate in atherosclerotic lesions and other sites of chronic inflammation, activates endothelial cells (EC) to bind monocytes by activation of endothelial ß1 integrin and subsequent deposition of fibronectin on the apical surface. Our previous studies suggest this function of OxPAPC is mediated via a Gs protein–coupled receptor (GPCR). PEIPC (1-palmitoyl-2-epoxyisoprostane E2-sn-glycero-3-phosphorylcholine) is the most active lipid in OxPAPC that activates this pathway. We screened a number of candidate GPCRs for their interaction with OxPAPC and PEIPC, using a reporter gene assay; we identified prostaglandin E2 receptor EP2 and prostaglandin D2 receptor DP as responsive to OxPAPC. We focused on EP2, which is expressed in ECs, monocytes, and macrophages. OxPAPC component PEIPC, but not POVPC, activated EP2 with an EC50 of 108.6 nmol/L. OxPAPC and PEIPC were also able to compete with PGE2 for binding to EP2 in a ligand-binding assay. The EP2 specific agonist butaprost was shown to mimic the effect of OxPAPC on the activation of ß1 integrin and the stimulation of monocyte binding to endothelial cells. Butaprost also mimicked the effect of OxPAPC on the regulation of tumor necrosis factor-
and interleukin-10 in monocyte-derived cells. EP2 antagonist AH6809 blocked the activation of EP2 by OxPAPC in HEK293 cells and blocked the interleukin-10 response to PEIPC in monocytic THP-1 cells. These results suggest that EP2 functions as a receptor for OxPAPC and PEIPC, either as the phospholipid ester or the released fatty acid, in both endothelial cells and macrophages.
Key Words: OxPAPC • GPCR • EP2 • monocyte binding • receptor • atherosclerosis
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