A rancid culprit in vascular inflammation acts on the prostaglandin receptor EP2.

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-2arachidonoyl-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-2epoxyisoprostane-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 G scoupled receptor, increasing cyclic AMP (cAMP) levels in endothelial cells.5,6 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, thus mimicking effects of an EP2specific PGE2 analogue, butaprost. Furthermore, PEIPC was also recognized by the PGD2 receptor DP. There are 4 subtypes of the PGE2 receptor, termed EP1 to EP4. EP2 is a G s-linked GPCR whose activation results in an increase of cAMP levels and activation of protein kinase A. Activation of this pathway in endothelial cells would, as previously shown, result in activation of R-Ras and 1integrins, leading to surface expression of CS-1 fibronectin, which then could readily interact with VLA-4 on monocytes (Figure 2). In monocytes, upregulation of cAMP levels via activation of EP2 by PEIPC resulted in downregulation of TNF and concomitant upregulation of IL-10 expression, characteristics of alternatively activated macrophages. Induction of this antiinflammatory phenotype would also prevent apoptosis, which is necessary for the monocyte/macrophage to become a foam cell (Figure 2). These findings imply that initiation of monocytic vascular inflammation can occur via activation of EP2 even in the absence of cyclooxygenase (COX)-derived PGE2, through formation of the oxidized phospholipid PEIPC. In a more advanced stage of atherogenesis, where monocytes/macrophages accumulate in the subendothelial space, activation of the EP2 receptor may occur by PEIPC, but also by COX-derived PGE2. There are a number of intriguing questions that remain to be addressed regarding EP receptor activation by PEIPC versus PGE2. The authors show that PEIPC competes with PGE2 for binding to EP2, and while PEIPC seems to be specific for EP2, PGE2 would also bind to EP1, 3, and 4. Activation of EP4 in macrophages stimulates antiinflammatory pathways via increasing cAMP levels,8 whereas in T-cells, for instance, EP4 can also stimulate proinflammatory cAMP-independent pathways.9 Consequently, the presence of both PGE2 and PEIPC would result in dual activation of EP2 and EP4 receptors in macrophages, likely potentiating antiinflammatory effects. However, in other cell types the relative abundance of the two EP ligands may determine stimulation of individual receptor subtypes and thus the outcome of cell activation. Moreover, it is conceivable that specific activation of EP2 by PEIPC would buffer proinflammatory effects elicited by EP1 and EP3 receptor activation by PGE2. The findings of the present study suggest that PEIPC–EP2 interactions may be important in vascular inflammation, and its pathophysiological relevance could be tested directly in vivo, for example in models of atherosclerosis. Future studies using mice deficient in EP2 and selective inhibitors should demonstrate whether PEIPC uses the EP2 receptor to induce vascular inflammation, and thus will affect the progression of atherosclerotic lesion formation. Moreover, because EP2 plays important roles not only in inflammation but also in blood pressure homeostasis and reproduction, as illustrated by genetic deletion of this receptor in mice,10,11 a role for The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Robert M. Berne Cardiovascular Research Center and Department of Pharmacology, University of Virginia, Charlottesville. Correspondence to Norbert Leitinger, PhD, Robert M. Berne Cardiovascular Research Center, University of Virginia, P.O. Box 801394, Charlottesville, VA 22908. E-mail [email protected]. (Circ Res. 2006;98:587-589.) © 2006 American Heart Association, Inc.