Oxidized PLs and Vascular Inflammation

Authors: Maceler Aldrovandi Valerie B O’Donnell

Publish Date: 2013/03/20

Volume: 15, Issue: 5, Pages: 323-

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Abstract

Oxidized PLs OxPLs generated in health and disease are now recognized as important mediators of cellular signalling There is an increasing body of evidence showing that PL peroxidation is not only increased in vascular disorders but is also a physiological event of relevance to coagulation innate immunity and selftolerance Nonenzymatically formed OxPLs generated during chronic inflammation is an uncontrolled event generating hundreds of diverse structures and prone to more deleterious bioactivities In contrast enzymatic formation of OxPLs is tightly regulated involving receptors and intracellular signaling acting as part of the normal physiological response to injury in order to restore homeostasis In the present review the major nonenzymatic OxPLs structures found during vascular inflammation are summarized along with a brief description of their known biological activities Also we review what is currently known about enzymatic formation of OxPLs by acutely activated immune cells and their signaling actions under homeostatic and pathological conditionsPhospholipids PLs are the major components of cell membranes and play a crucial role in the biochemistry of all living cells They provide a permeable barrier as well as acting as substrates for the synthesis of essential signalling mediators such as eicosanoids PLs consist of a glycerol backbone connected to two nonpolar fatty acids at sn1 and sn2 and a phosphatecontaining polar headgroup at the sn3 position In mammalian cells polyunsaturated fatty acids are usually bound to the sn2 of glycerol where the majority of oxidation will occur Oxidation of esterified polyunsaturated fatty acids can be initiated via both enzymatic and nonenzymatic mechanisms and can form hundreds of diverse structures 1•• 2 Phosphatidylcholine PC is the most abundant PL species in eukaryotic cell membranes 40–50  and as a result the vast proportion of nonenzymaticallyformed OxPLs detected in mammalian tissues contain the choline headgroup In contrast phosphatidylethanolamine PE is the prominent PL class modified via enzymatic oxidation 37OxPLs exhibit a vast range of biological activities including acting as markers of “modifiedself” that can induce apoptotic and senescent cell removal and more complex interactions such as regulation of immune responses 1•• 2 Their involvement in activation of platelet aggregation and monocyte adhesion as well as suppression of cytokine generation and neutrophil superoxide release has been reported 8 9 10 11 12 Also they can act as both pro and antiinflammatory mediators during the progression of atherosclerosisNonenzymatically oxidized PLs that derive from PL hydroperoxide decomposition have been measured in atherosclerotic lesions of humans and other mammalian models of atherosclerosis 1•• 13 14 15 16 17 LCMS analysis of human atheroma at different stages of development identified similar OxPL species at different stages of the disease 18 The detection of early oxidation species like hydroperoxides and further oxidized products such as fragmented OxPLs suggests that during the development of atherosclerotic lesions nonenzymatically formed OxPLs are continuously being formed through hydroperoxide decomposition Even though this is expected to be an uncontrolled event whether the initial hydroperoxides originate from oxidation reactions driven by enzymatic or nonenzymatic processes in vivo remain unknownEnzymatically formed OxPLs are generated by proteins that are conserved among all mammalian species such as lipoxygenases LOX and cyclooxygenases COX and their synthesis involves receptors and intracellular signalling pathways 1•• 19•• Tight control of this process and associated biological actions of the products observed in vitro indicates that these lipids are of physiological importance and likely to play a role in innate immune defences and haemostasis see below In contrast nonenzymatic oxidized PLs are generated in diseases characterized by chronic inflammation such as atherosclerosis where the enhanced production of free radicals as a result of immune cells activation leads to uncontrolled oxidant toxicity In both circumstances common bioactivities are displayed with both classes likely being important in human health and diseaseIn this review we summarise the major nonenzymatic OxPL structures found during vascular inflammation and we give a brief description of their known biological activities Then we focus on what is known about enzymatic formation of OxPLs generated by acutely activated immune cells and their signaling actions in health and diseaseAtherosclerosis is a chronic vascular disorder characterized by an accumulation of lipids in the artery wall and persistent inflammation 20• The initiation and progression of the disease is controlled by inflammatory molecular and cellular mediators which often trigger oxidative damage to biological molecules Enhanced production of free radicals including reactive oxygen species ROS generated by activated phagocytes results in increased levels of OxPLs which have been detected in human atherosclerotic lesions 13 21

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