Import and fate of fluorescent analogs of oxidized phospholipids in vascular smooth muscle cells

Moumtzi, Alexandra; Trenker, Michael; Flicker, Karlheinz; Zenzmaier, Elfriede; Saf, Robert; Hermetter, Albin

doi:10.1194/jlr.m600394-jlr200

Cited by 47 publications

(40 citation statements)

References 47 publications

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“…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.…”

Section: Chemistry Of Oxidized Phospholipidsmentioning

confidence: 96%

The role of oxidized phospholipids in atherosclerosis

Berliner

Leitinger

Tsimikas

2009

Journal of Lipid Research

220

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: Chemistry Of Oxidized Phospholipidsmentioning

confidence: 96%

The role of oxidized phospholipids in atherosclerosis

Berliner

Leitinger

Tsimikas

2009

Journal of Lipid Research

220

110

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“…the activation of apoptotic signaling pathways (6). Fast uptake of synthetic PGPC analogues to the perinuclear region of vascular smooth muscle cells has been reported (7) and discussed in view of its ability to activate acid sphingomyelinase (8). The uptake mechanism and sites of action, however, still remain enigmatic.…”

mentioning

confidence: 99%

Plasma Membrane Fluidity Affects Transient Immobilization of Oxidized Phospholipids in Endocytotic Sites for Subsequent Uptake

Rhode¹,

Grurl²,

Brameshuber³

et al. 2009

Journal of Biological Chemistry

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Oxidized phospholipids in serum initiate severe pathophysiological responses during the process of atherogenesis. On the cellular level it is known that these lipids induce apoptosis; however, the uptake mechanism remains enigmatic. We investigated here the behavior of the fluorescent oxidized phospholipid 1-palmitoyl-2-glutaroyl-sn-glycero-3-phospho-NAlexa647-ethanolamine (PGPE-Alexa647) in the plasma membrane of various cell lines. The probe was taken up by the cells unspecifically via caveolae or clathrin-coated pits. Interestingly, we found the uptake to be facilitated by the overexpression of the scavenger receptor class B type I. Ultra-sensitive microscopy allowed us to follow the uptake process at the single molecule level; we observed rapid diffusion of PGPE-Alexa647 in the plasma membrane, interrupted by transient halts with duration of ϳ0.9 s at endocytotic sites. Scavenger receptor class B type I overexpression yielded a pronounced increase in the single molecule mobility, and in consequence an increased frequency of immobilization. Alternatively, the plasma membrane fluidity could also be increased by treating cells with high levels of the unlabeled oxidized phospholipid 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphocholine; also in this case, the immobilization frequency of PGPE-Alexa647 was concomitantly increased. The data demonstrate the relevance of plasma membrane properties for uptake of oxidized phospholipids, and indicate a novel indirect mechanism for the control of endocytosis. Oxidation of low density lipoprotein (LDL)2 is known to be a key step in atherogenesis, leading to inflammation, proliferation, and apoptosis of cells of the arterial wall. These effects are largely exerted by oxidatively fragmented phospholipids, which are highly exchangeable between cells, tissues, and lipoproteins (1-5). In particular, 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphocholine (PGPC) has been identified in minimally modified LDL and has been reported to elicit a wide range of pathophysiological responses in vascular cells, e.g. the activation of apoptotic signaling pathways (6). Fast uptake of synthetic PGPC analogues to the perinuclear region of vascular smooth muscle cells has been reported (7) and discussed in view of its ability to activate acid sphingomyelinase (8). The uptake mechanism and sites of action, however, still remain enigmatic.PGPC carries an acyl fragment in the sn-2 position, which represents the oxidation product of an unsaturated acyl chain. This hydrophilic side chain is expected to be folded to the polar region of the membrane, yielding a structure best described by a lysolipid-like inverted cone (7). Addition of such nonbilayer lipids to model membranes is known to bend lipid monolayers, and it may well assist in the formation of highly curved structures also in cell membranes (9). In turn, such lipids are expected to become energetically trapped and thereby enriched in bent membrane regions (9 -12). It can therefore be expected that local enrichment of PGPC may exert dramatic chan...

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“…This class of truncated phospholipid favors a robust inflammatory response that would augment reactive oxygen species production. Oxidatively truncated phospholipids also affect cellular homeostasis by reducing mitochondrial integrity and function (12,13). A common truncation product of HpODE residues esterified at the sn-2 position is an esterified sn-2 azelaoyl fragment, and this oxidatively truncated phospholipid is particularly mitotoxic and effectively initiates the intrinsic caspase cascade leading to apoptotic cell death (14,15).…”

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confidence: 99%

Chronic Alcohol Exposure Increases Circulating Bioactive Oxidized Phospholipids

Yang

Latchoumycandane

McMullen

et al. 2010

Journal of Biological Chemistry

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Ethanol metabolism by liver generates short lived reactive oxygen species that damage liver but also affects distal organs through unknown mechanisms. We hypothesized that dissemination of liver oxidative stress proceeds through release of biologically active oxidized lipids to the circulation. We searched for these by tandem mass spectrometry in plasma of rats fed a Lieber-DeCarli ethanol diet or in patients with established alcoholic liver inflammation, steatohepatitis. We found a severalfold increase in plasma peroxidized phosphatidylcholines, inflammatory and pro-apoptotic oxidatively truncated phospholipids, and platelet-activating factor, a remarkably potent and pleiotropic inflammatory mediator, in rats chronically ingesting ethanol. Circulating peroxidized phospholipids also increased in humans with established steatohepatitis. However, reactive oxygen species generated by liver ethanol catabolism were not directly responsible for circulating oxidized phospholipids because the delayed appearance of these lipids did not correlate with ethanol exposure, hepatic oxidative insult, nor plasma alanine transaminase marking hepatocyte damage. Rather, circulating oxidized lipids correlated with steatohepatitis and tumor necrosis factor-␣ deposition in liver. The organic osmolyte 2-aminoethylsulfonic acid (taurine), which reduces liver endoplasmic reticulum stress and inflammation, even though it is not an antioxidant, abolished liver damage and the increase in circulating oxidized phospholipids. Thus, circulating oxidized phospholipids are markers of developing steatohepatitis temporally distinct from oxidant stress associated with hepatic ethanol catabolism. Previously, circulating markers of the critical transition to pathologic steatohepatitis were unknown. Circulating oxidatively truncated phospholipids are pro-inflammatory and pro-apoptotic mediators with the potential to systemically distribute the effect of chronic ethanol exposure. Suppressing hepatic inflammation, not ethanol catabolism, reduces circulating inflammatory and apoptotic agonists.

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Import and fate of fluorescent analogs of oxidized phospholipids in vascular smooth muscle cells

Cited by 47 publications

References 47 publications

The role of oxidized phospholipids in atherosclerosis

The role of oxidized phospholipids in atherosclerosis

Plasma Membrane Fluidity Affects Transient Immobilization of Oxidized Phospholipids in Endocytotic Sites for Subsequent Uptake

Chronic Alcohol Exposure Increases Circulating Bioactive Oxidized Phospholipids

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