A Rancid Culprit in Vascular Inflammation Acts on the Prostaglandin Receptor EP2

Abstract

See related article, pages 642–650 Although our knowledge about the mechanisms underlying atherosclerosis and its complications has dramatically increased, questions about the initiating factors of atherogenesis remain. Accumulating evidence suggests retention of low-density lipoprotein (LDL) particles in the subendothelial space with subsequent oxidative modification as key steps in atherogenesis. Oxidative modification initially gives rise to minimally oxidized LDL (MM-LDL), which was shown by Judy Berliner in 1990 to activate endothelial cells to specifically bind monocytes but not neutrophils.1 It was subsequently shown by the same group that the biological activity of MM-LDL primarily results from oxidation of phospholipids such as 1-palmitoyl-2-arachidonoyl- sn -3-glycero-phosphorylcholine (PAPC), yielding a series of structurally defined oxidation products (OxPAPC). The advances that have been made in dissecting the molecular components of MM-LDL responsible for its proatherogenic effect now allow for the experimental use of defined compounds rather than complex lipoproteins. One such biologically active oxidized phospholipid was structurally identified by Watson et al as 1-palmitoyl-2-epoxyisoprostane- sn -glycero-3-phosphorylcholine (PEIPC; Figure 1).2,3 Oxidized (“rancid”) phospholipids were shown to accumulate in atherosclerotic lesions,4 and thus could be regarded as “culprits” in chronic inflammation. Although intracellular signaling pathways induced by various oxidized phospholipids had been studied, target receptors that are activated by these lipids remained unknown. Indications that oxidized phospholipids may act by binding to a G protein–coupled receptor (GPCR) came from studies by Parhami et al, who demonstrated that MM-LDL stimulates a putative Gαs-coupled receptor, increasing cyclic AMP (cAMP) levels in endothelial cells.5,6 Figure 1. Structures of 1-palmitoyl-2-arachidonoyl-sn-3-glycero-phosphorylcholine (PAPC), and 1-palmitoyl-2-epoxyisoprostane-sn-glycero-3-phosphorylcholine (PEIPC). In this issue of Circulation Research , Li et al7 demonstrate that the oxidized phospholipid PEIPC induces monocyte adhesion to endothelial cells by activating the prostaglandin E2 (PGE2) receptor EP2. Activation of EP2 by PEIPC increased cAMP levels, …