Modification of LDL with oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (oxPAPC) results in a novel form of minimally modified LDL that modulates gene expression in macrophages

Groeneweg, Mathijs; Vergouwe, Monique N.; Scheffer, P; Vermue, Hendrikus P.A.; Gelpke, Maarten D. Sollewijn; Sijbers, Anneke M.; Leitinger, Norbert; Hofker, Marten H.; Winther, Menno P.J. de

doi:10.1016/j.bbalip.2008.04.016

Cited by 14 publications

(12 citation statements)

References 31 publications

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“…Several groups have shown that LDL supplemented with Ox-PAPC or vesicles supplemented with fragmented a/b unsaturated fatty acids at the sn-2 position, such as KOdiA or HODA PC, bind to CD36 (2,20). In these experiments, as little as 0.3 mol% of HDdiA PC was sufficient to cause CD36 binding.…”

Section: Macrophagesmentioning

confidence: 64%

“…Mechanisms of induction of pro-apoptotic pathways by OxPL have been reviewed recently (28). However, in atherosclerotic lesions, where macrophages are constantly exposed to high levels of OxPLs, macrophages survive for surprisingly long periods of time, despite the toxic environment, implying the upregulation of survival mechanisms, such as antioxidant pathways and phase II detoxification genes, some of which have been observed (12,20).…”

Section: Macrophagesmentioning

confidence: 99%

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The role of oxidized phospholipids in atherosclerosis

Berliner

Leitinger

Tsimikas

2009

Journal of Lipid Research

Self Cite

226

110

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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...

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Section: Macrophagesmentioning

confidence: 64%

Section: Macrophagesmentioning

confidence: 99%

The role of oxidized phospholipids in atherosclerosis

Berliner

Leitinger

Tsimikas

2009

Journal of Lipid Research

Self Cite

226

110

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“…Oxidized LDL and DiI-labeled oxLDL were prepared from pooled human plasma and labeled as described. 39 …”

Section: Methodsmentioning

confidence: 99%

Microparticles from apoptotic platelets promote resident macrophage differentiation

et al. 2011

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Platelets shed microparticles not only upon activation, but also upon ageing by an apoptosis-like process (apoptosis-induced platelet microparticles, PMap). While the activation-induced microparticles have widely been studied, not much is known about the (patho)physiological consequences of PMap formation. Flow cytometry and scanning electron microscopy demonstrated that PMap display activated integrins and interact to form microparticle aggregates. PMap were chemotactic for monocytic cells, bound to these cells, an furthermore stimulated cell adhesion and spreading on a fibronectin surface. After prolonged incubation, PMap promoted cell differentiation, but inhibited proliferation. Monocyte membrane receptor analysis revealed increased expression levels of CD11b (integrin αMβ2), CD14 and CD31 (platelet endothelial cell adhesion molecule-1), and the chemokine receptors CCR5 and CXCR4, but not of CCR2. This indicated that PMap polarized the cells into resident M2 monocytes. Cells treated with PMap actively consumed oxidized low-density lipoprotein (oxLDL), and released matrix metalloproteinases and hydrogen peroxide. Further confirmation for the differentiation towards resident professional phagocytes came from the finding that PMap stimulated the expression of the (ox)LDL receptors, CD36 and CD68, and the production of proinflammatory and immunomodulating cytokines by monocytes. In conclusion, interaction of PMap with monocytic cells has an immunomodulating potential. The apoptotic microparticles polarize the cells into a resident M2 subset, and induce differentiation to resident professional phagocytes.

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“…45 In the current study we did not measure oxPAPC in LDL fraction although prior studies have demonstrated increased oxPAPC in circulating lipoproteins including LDL and HDL. 46, 47 Although oxPAPC may not be the major component of oxLDL or oxidized lipids within plaque, it certainly may represent an additional oxidation product that is delivered via scavenger receptors and may accumulate within atherosclerosis. Additionally the presence of oxPAPC may result in pro-inflammatory effects within the vascular wall.…”

Section: Discussionmentioning

confidence: 99%

CD36-Dependent 7-Ketocholesterol Accumulation in Macrophages Mediates Progression of Atherosclerosis in Response to Chronic Air Pollution Exposure

Rao

Zhong

Maiseyeu

et al. 2014

Circulation Research

164

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Rationale Air pollution exposure has been shown to potentiate plaque progression in humans and animals. Our previous studies have suggested a role for oxidized lipids in mediating adverse vascular effect of air pollution. However, the types of oxidized lipids formed in response to air pollutants and how this occurs and their relevance to atherosclerosis is not fully understood. Objective To investigate the mechanisms by which particulate matter< 2.5μm (PM2.5) induces progression of atherosclerosis. Methods and Results Atherosclerosis-prone ApoE−/− or LDLR−/− mice were exposed to filtered air or concentrated ambient PM2.5 using a versatile aerosol concentrator enrichment system for 6 months. PM2.5 increased 7-ketocholesterol (7-KCh), an oxidatively modified form of cholesterol, in plasma IDL/LDL fraction and in aortic plaque concomitant with progression of atherosclerosis and increased CD36 expression in plaque-macrophages from PM2.5-exposed mice. Macrophages isolated from PM2.5-exposed mice displayed increased uptake of oxidized lipids without alterations in their efflux capacity. Consistent with these finding, CD36-positive macrophages displayed a heightened capacity for oxidized lipid uptake. Deficiency of CD36 on hematopoietic cells diminished the effect of air pollution on 7-KCh accumulation, foam cell formation, and atherosclerosis. Conclusions Our results suggest a potential role for CD36-mediated abnormal accumulations of oxidized lipids such as 7-KCh in air pollution induced atherosclerosis progression.

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Modification of LDL with oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (oxPAPC) results in a novel form of minimally modified LDL that modulates gene expression in macrophages

Cited by 14 publications

References 31 publications

The role of oxidized phospholipids in atherosclerosis

The role of oxidized phospholipids in atherosclerosis

Microparticles from apoptotic platelets promote resident macrophage differentiation

CD36-Dependent 7-Ketocholesterol Accumulation in Macrophages Mediates Progression of Atherosclerosis in Response to Chronic Air Pollution Exposure

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