The role of oxidized phospholipids in atherosclerosis

Abstract

There is increasing evidence that oxidized phospholipids (OxPLs) play an important role in atherosclerosis. These phospholipids accumulate in human and mouse lesions. Specific OxPLs have been identified as major regulators of many cell types present in the vessel wall. In endothelial cells, .1,000 genes are regulated. Some of these genes are pro-atherogenic and others anti-atherogenic. The anti-atherogenic effects are likely important in slowing the atherogenic process. Several receptors and signaling pathways associated with OxPL action have been identified and shown to be upregulated in human lesions. A structural model of the mechanism by which specific OxPLs serve as CD36 ligands has been identified. Specific oxidized phospholipids are also present in plasma and associated with Lp(a) particles. In humans, OxPL/apolipoprotein B has been shown to be a prognostic indicator and a separate risk factor for coronary events. CHEMISTRY OF OXIDIZED PHOSPHOLIPIDSSeveral reviews and original articles have identified the structure of bioactive oxidized phospholipids that are formed from PUFAs at the sn-2 position (1-3). The number of oxidation products from each PUFA is likely at least 50, and effects of all of these products have not been examined. For the purposes of this review, we will only include structures of several well-studied molecules (Fig. 1). Bioactive oxidized phospholipids may contain fragmentation products of PUFA, such as 1-palmitoyl-2-oxovaleroyl-sn-glycero-3-phoshorylcholine and 9-keto-10-dodecendioic acid ester of 2-lyso-phosphatidyl choline (KOdiA-PC); prostaglandins, such as 15 deoxy-delta12,14 prostaglandin J2 (PGJ2) and 1-palmitoyl-2-(5,6-epoxyisoprostane E2)-sn-glycero-3-phosphoryl choline (PEIPC); and levuglandins. These molecules exhibit different biological activities. An important recent development is a better understanding of the initial interaction of oxidized phospholipids with cells. Receptors have been identified, including CD36, SRB1, EP2, VEGFR2, and the PAF receptor (1, 4). An interaction with TLR4 has also been suggested in some studies but not others (1, 5). A possible mechanism by which cells recognize oxidized phospholipids has been suggested involving the novel confirmation of these lipids in membranes (6). These studies demonstrated that, when present in vesicles, truncated oxidized fatty acids at the sn-2 position move from the hydrophobic interior to the aqueous exterior of the vesicle. This would allow their recognition by cell surface receptors. An earlier model of isoprostane-containing phospholipids suggests that they are highly twisted and may distort membrane areas in which they are present (7). These studies and others (8) suggest that phospholipid oxidation products can integrate into lipid membranes of cells and lipoproteins; they then can either act as ligands or may cause local membrane disruption. In addition, strong evidence has been presented for the ability of oxidized phospholipids to form protein adducts. Probably the most well characterized are th...

The effect of oxidized phospholipids on phenotypic polarization and function of macrophages

“…In this study the authors describe that even trace amounts of oxPC CD36 are enough to induce CD36-dependent binding and uptake of LDL[28]. Accumulating evidence suggests that biologically active OxPL that are present in atherogenic lipoproteins, in atherosclerotic lesions, and in membrane vesicles released from activated and apoptotic cells play an essential role in the development of atherosclerosis [14, 29, 30]. Indeed, OxPL affect a variety of vascular cell types, including endothelial [31–36] and smooth muscle [37–39] cells.…”

“…After the identification of OxPL as biologically active components of minimally oxidized LDL[8, 9], OxPL have been ascribed pro- as well as anti-inflammatory properties, depending on their structural features and functional groups, which also determine their recognition by extracellular or intracellular receptors. The effects of OxPL on modulation of inflammatory responses have been extensively reviewed[10–14], however, little is known about the mechanisms that control the formation and degradation of OxPL in different cell types. Moreover, the effects oxidized lipids have on cells of the immune system are poorly understood.…”

Computational Investigation of Darapladib and Rilapladib Binding to Platelet Activating Factor Receptor. A Possible Mechanism of Their Involvement in Atherosclerosis

“…In vitro studies involving PAF-like lipids that are mostly fragmented and/or oxidized sn-2 fatty acyl groups and their hydrolysis products, have shown that these molecules can act both as pro-and anti-inflammatory mediators (Berliner, Leitinger, & Tsimikas, 2009;Feige, Mendel, George, Yacov, & Harats, 2010). These studies though do not take into consideration the fact that lyso-PC and free fatty acids are associated with lipoproteins and other plasma carriers making it difficult to calculate their exact concentration and bioavailability in plasma (Öörni & Kovanen, 2009;Rosenson & Stafforini, 2012).…”

The remineralization of marine organic matter by diverse biological and abiotic processes

“…While fragments diagnostic of specific oxidation types and positions are sometimes observed in the MS 2 spectra of oxidized phospholipids, spectra obtained from successive fragmentation of target ions at levels > MS 2 are needed to definitively resolve the structures of many ox-PC species. A significant and growing body of literature offers a wealth of information for analysis of MS 3 and higher-level data obtained under a variety of HPLC-MS methods in both positive and negative ionization modes (Berliner et al, 2009;Buseman et al, 2006;Domingues et al, 2008;Ishida et al, 2004;Milic et al, 2012;L. T. Morgan et al, 2010;Ni et al, 2015;O'Donnell, 2011;Reis and Spickett, 2012;Sala et al, 2015;Spickett and Dever, 2005;Spickett et al, 2011;Thomas et al, 2010;Yin et al, 2009).…”