A role for phospholipid oxidation products as modulators of inflammatory reactions in atherogenesis

Abstract

In 1990 Berliner et al. demonstrated that LDL that had been mildly oxidized by prolonged storage or using iron had unique properties different from those of native and oxidized LDL (oxLDL). This LDL was called minimally oxidized or minimally modified LDL (MM-LDL) and shown to have unique bioactivity such as: induction of monocyte-endothelial interactions, expression of MCP-1, monocyte transmigration. 1-palmitoyl -2-archidonoyl-sn-glycero-3-phosphocholine (PAPC) is an arachidonic acid-containing phospholipid especially prone to oxidation. Biologically active oxidized derivatives of PAPC were identified as 1-palmitoyl-2-(5 -oxovaleryl)-sn-glycero-3-phosphocholine (POVPC) and 1-palmitoyl-2-glutaryl-sn-glycero-3-phosphocholine (PGPC) and epoxyisoprostane PC. Upon stimulation with various agonists or lipid oxidation, eukaryotic cells release membrane vesicles (MV) into the extracellular space due to increase in intracellular calcium and loss of membrane asymmetry. Membrane vesicles are also carriers of the bioactive lipids. Oxidized lipids may inhibit acute, but promote chronic inflammation. There is evidence that LPS-induced NFkB-mediated inflammation is down regulated by OxPAPC. Oxidized phospholipids increase synthesis of EGR-1. EGR-1 is known to be up regulated by growth factors, cytokines, hypoxia, physical forces and injurious stimuli, and high levels of EGR-1 were found in atherosclerotic lesions. EGR-1 up-regulates expression of TF. In contrast to the up-regulation of proinflammatory genes, oxidized phospholipids were also shown to induce the expression of protective enzymes such as HO-l, which is the rate-limiting enzyme in heme-catabolism and has antioxidative capacity. Thus, identification of mechanisms and signaling pathways induced by oxidized lipids that modulate inflammatory response in the vascular wall will lead to novel strategies of therapeutic intervention in chronic inflammatory diseases.