Published online before print February 2, 2006, doi: 10.1161/01.RES.0000207394.39249.fc
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Submitted on July 8, 2005
Revised on January 6, 2006
Accepted on January 20, 2006
Identification of Prostaglandin E2 Receptor Subtype 2 As a Receptor Activated by OxPAPC
Rongsong Li ;
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.
* To whom correspondence should be addressed. 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 
1 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 1 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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