Evidence that phospholipid oxidation products and/or platelet-activating factor play an important role in early atherogenesis - In vitro and in vivo inhibition by WEB 2086

The goal of the present studies was to determine whether phospholipid oxida tion products and/or platelet-activating factor (PAF) are mediators of earl y atherogenesis in vivo. Monocyte-endothelial cell interactions have been s hown to play an important role in early atherogenesis. We and others have d emonstrated that PAF and phospholipid oxidation products, present in athero sclerotic lesions, including 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-pho sphocholine (POVPC), 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphocholine (P GPC), and 1-palmitoyl-2-epoxyisoprostane E-2-sn-glycero-3-phosphocholine (P EIPC), mediate the activation of monocytes and/or endothelial cells in vitr o. Previous studies have shown that the action of PAF and PAF-like ether-co ntaining phospholipids was inhibited by WEB 2086. We now demonstrate that p retreatment of human aortic endothelial cells with WEB 2086 (10 mu mol/L) a nd several other PAF antagonists before treatment with POVPC and PEIPC but not PGPC prevented the activation of the endothelial cells to bind monocyte s. We present evidence to suggest that this inhibition is not mediated by t he PAF receptor. The role of bioactive oxidized phospholipids in fatty stre ak formation was tested using C57BL/6J LDL R-/- mice fed a chow or Western diet for 5 weeks with or without WEB 2086 mixed with drinking water. Quanti tative electrospray ionization mass spectrometry showed similar concentrati ons of WEB 2086 in the plasma of mice on both diets (approximate to 4 to 5 mu mol/L); this concentration was inhibitory in vitro. Administration of WE B 2086 did not affect the lipid composition of mouse plasma. However, fatty streak formation was reduced by 62% in animals fed a Western diet, whereas no change was observed in the small lesions of mice on a chow diet. These studies provide evidence that PAF and/or PAF-like phospholipid oxidation pr oducts are important mediators of atherosclerotic lesion development in viv o and that specific receptor antagonists for these molecules may represent a novel therapeutic modality.