(Carboxyalkyl)pyrroles in Human Plasma and Oxidized Low-Density Lipoproteins

Kaur, Kamaljit; Salomon, Robert G.; O’Neil, June; Hoff, Hans

doi:10.1021/tx970112c

Cited by 104 publications

(132 citation statements)

References 30 publications

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“…CEP protein adducts belong to a family of 2-(-carboxyalkyl) pyrrole adducts generated from the oxidation of PUFAs (21). For example, oxidative fragmentation of linoleic acid or arachidonic acid can generate 2-(-carboxyheptyl)pyrrole or 2-(-carboxypropyl)pyrrole adducts, respectively.…”

Section: Discussionmentioning

confidence: 99%

Carboxyethylpyrrole oxidative protein modifications stimulate neovascularization: Implications for age-related macular degeneration

Ebrahem

Renganathan

Sears

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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108

129

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Choroidal neovascularization (CNV), the advanced stage of age-related macular degeneration (AMD), accounts for >80% of vision loss in AMD. Carboxyethylpyrrole (CEP) protein modifications, uniquely generated from oxidation of docosahexaenoate-containing lipids, are more abundant in Bruch’s membrane from AMD eyes. We tested the hypothesis that CEP protein adducts stimulate angiogenesis and possibly contribute to CNV in AMD. Human serum albumin (HSA) or acetyl-Gly-Lys- O -methyl ester (dipeptide) were chemically modified to yield CEP-modified HSA (CEP-HSA) or CEP-dipeptide. The in vivo angiogenic properties of CEP-HSA and CEP-dipeptide were demonstrated by using the chick chorioallantoic membrane and rat corneal micropocket assays. Low picomole amounts of CEP-HSA and CEP-dipeptide stimulated neovascularization. Monoclonal anti-CEP antibody neutralized limbal vessel growth stimulated by CEP-HSA, whereas anti-VEGF antibody was found to only partially neutralize vessel growth. Subretinal injections of CEP-modified mouse serum albumin exacerbated laser-induced CNV in mice. In vitro treatments of human retinal pigment epithelial cells with CEP-dipeptide or CEP-HSA did not induce increased VEGF secretion. Overall, these results suggest that CEP-induced angiogenesis utilizes VEGF-independent pathways and that anti-CEP therapeutic modalities might be of value in limiting CNV in AMD.

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Section: Discussionmentioning

confidence: 99%

Carboxyethylpyrrole oxidative protein modifications stimulate neovascularization: Implications for age-related macular degeneration

Ebrahem

Renganathan

Sears

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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108

129

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“…Recent studies examining products formed during oxidation of free polyunsaturated fatty acids demonstrated that 5-hydroxy-8-oxo-6-octenoic acid (HOOA) and 9-hydroxy-12-oxo-10 dodecenoic acid (HODA) are co-produced in yields similar to 4-HNE during free radical oxidation of arachidonic and linoleic acids, respectively (38, 58). Based upon this observation, it was postulated that by analogy to the formation of 4-HNE, HOOA-PC and HODA-PC might be formed during free radical oxidation of PAPC and PLPC, respectively (59). Antibodies raised against proteins modified by sn-2 ␣,␤-unsaturated, ␥-hydroxycarbonyl-containing PCs were generated and used to demonstrate the presence of similar epitopes within LDL oxidized in vitro and in plasma proteins recovered from individuals with atherosclerosis (59).…”

Section: Discussionmentioning

confidence: 99%

Identification of a Novel Family of Oxidized Phospholipids That Serve as Ligands for the Macrophage Scavenger Receptor CD36

Podrez¹,

Poliakov²,

Shen³

et al. 2002

Journal of Biological Chemistry

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468

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The macrophage scavenger receptor CD36 plays an important role in the uptake of oxidized forms of low density lipoprotein (LDL) and contributes to lesion development in murine models of atherosclerosis. However, the structural basis of CD36 lipoprotein ligand recognition is unknown. We now identify a novel class of oxidized phospholipids that serve as high affinity ligands for CD36 and mediate recognition of oxidized forms of LDL by CD36 on macrophages. Small unilamellar vesicles of homogeneous phosphatidylcholine (PC) molecular species were oxidized by the myeloperoxidase (MPO)-H 2 O 2 -NO 2 ؊ system, and products were separated by sequential LC/ESI/MS/MS. In parallel, fractions were tested for their ability to bind to CD36. Four major structurally related phospholipids with CD36 binding activity were identified from oxidized 1-palmitoyl-2-arachidonyl-PC, and four corresponding structural analogs with CD36 binding activity were identified from oxidized 1-palmitoyl-2-linoleoyl-PC. Each was then synthetically prepared, its structure confirmed by multinuclear NMR and high resolution mass spectrometry, and shown to possess identical CD36 binding activity and LC/ESI/MS/MS characteristics in both native and derivatized forms. Based upon the structures of the active compounds identified, and structure-function studies with a variety of synthetic analogs, we conclude that the structural characteristics required for high affinity binding of oxidized PC species to CD36 are a phospholipid with an sn-2 acyl group that incorporates a terminal ␥-hydroxy(or oxo)-␣,␤-unsaturated carbonyl (oxPC CD36 ). LC/ESI/MS/MS studies demonstrate that oxPC CD36 are formed during LDL oxidation by multiple distinct pathways. Formation of this novel class of oxidized PC species contributes to CD36-mediated recognition of LDL oxidized by MPO and other biologically relevant mechanisms. The present results offer structural insights into the molecular patterns recognized by the scavenger receptor CD36 and provide a platform for the development of potential therapeutic inhibitory agents.CD36 is a heavily glycosylated, single chain, integral plasma membrane protein that belongs to an evolutionarily conserved family of proteins that serve as scavenger and lipid receptors (1, 2). It is expressed on the surface of adipocytes, microvascular endothelial cells, macrophages, platelets, and specialized epithelial cells (1, 2). CD36 functions in vivo in scavenger recognition of oxidized lipoproteins and senescent or apoptotic cells, fatty acid transport, cell-matrix interactions, and antiangiogenic actions (3-5). Its deficiency in humans has been correlated with alterations in myocardial fatty acid uptake, hypertrophic cardiac myopathy, and insulin resistance (6 -8). Recent studies (3, 4, 9 -11) have focused attention on CD36 as a participant in the atherosclerotic process because of its ability to recognize oxidized forms of LDL (oxLDL).1 CD36 mediates lipid accumulation and macrophage foam cell formation in vitro and in vivo (3,12,13). It is heavily expre...

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“…Increased plasma PP was reported in atherosclerosis and renal failure [22] . In the present study, serum PP was found to be higher in CCl 4 -treated rats and a similar study was not identified in the literature.…”

Section: Discussionmentioning

confidence: 99%

The Effect of N-acetylcysteine on Pyrrolized Protein, Lipid Hydroperoxide and Thiol Levels in the Carbon Tetrachloride Hepatotoxicity

Yazıcı¹,

Köse²

2016

ijps

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Yazici, et al.: N-acetylcysteine Effect on Oxidative Stress in RatsThis study was performed, on the rat model, to form oxidative stress by carbon tetrachloride and to reveal the relationship between toxicity and oxidative/thiol stresses through lipid/protein oxidation and to investigate the effects of N-acetylcysteine on the hepatotoxicity induced oxidative stress. Wistar albino male rats were divided into four groups as carbon tetrachloride, N-acetylcysteine, carbon tetrachloride-N-acetylcysteine and control, each of ten rats. Carbon tetrachloride (1.0 ml, 800 mg/kg; single dose) and N-acetylcysteine (200 mg; three doses) were intraperitoneally applied to corresponding groups as per kg of rat weight. Hepatotoxicity was identified with histopathological methods. Besides the thiol levels in plasma/tissue samples, pyrrolized protein and total lipid hydroperoxide levels in serum samples were measured. Carbon tetrachloride-induced hepatotoxic lesions remarkably improved in the presence of N-acetylcysteine. There was no significant difference between control and N-acetylcysteine groups, in terms of parameters measured in serum/plasma and tissue samples. When compared to these groups, pyrrolized protein and total lipid hydroperoxide levels were found to be higher; whereas plasma/tissue thiol levels lower in the carbon tetrachloride group. N-acetylcysteine in combination with carbon tetrachloride significantly lowered pyrrolized protein and total lipid hydroperoxide levels, and increased thiol levels, so that the values were reached to those of control and N-acetylcysteine groups. As reflected by higher pyrrolized protein and total lipid hydroperoxide, and lower thiol levels, enhanced free radical production in the carbon tetrachloride hepatotoxicity may lead to oxidative and thiol stresses mediated lipid/protein oxidation. In addition, N-acetylcysteine, a powerful antioxidant, may be added as a thiol source to the treatment protocols of several diseases whose pathogenesis is of oxidative and thiol stress.

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(Carboxyalkyl)pyrroles in Human Plasma and Oxidized Low-Density Lipoproteins

Cited by 104 publications

References 30 publications

Carboxyethylpyrrole oxidative protein modifications stimulate neovascularization: Implications for age-related macular degeneration

Carboxyethylpyrrole oxidative protein modifications stimulate neovascularization: Implications for age-related macular degeneration

Identification of a Novel Family of Oxidized Phospholipids That Serve as Ligands for the Macrophage Scavenger Receptor CD36

The Effect of N-acetylcysteine on Pyrrolized Protein, Lipid Hydroperoxide and Thiol Levels in the Carbon Tetrachloride Hepatotoxicity

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