Characterization of Linoleic Acid Nitration in Human Blood Plasma by Mass Spectrometry

Lima, Emersom Silva; Mascio, Paolo Di; Rubbo, Homero; Abdalla, Dulcinéia Saes Parra

doi:10.1021/bi025504j

Cited by 99 publications

(82 citation statements)

References 30 publications

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“…Plasma concentrations of free LNO 2 in normal healthy humans is Ϸ500 nM (3), and in this study concentrations of LNO 2 as low as 1 M were associated with HO-1 induction. Increased levels of 18:2 nitration products (nitrolinoleate and cholesteryl nitrolinoleate) are present in plasma from hyperlipidemic patients compared with normolipidemic patients (36,37). Using stable isotope dilution LC-mass spectrometry, current data indicate significantly increased levels of nitroalkenes in a variety of inflammatory conditions and animal models of inflammation (unpublished observations).…”

Section: Discussionmentioning

confidence: 84%

Fatty acid transduction of nitric oxide signaling: Nitrolinoleic acid potently activates endothelial heme oxygenase 1 expression

Wright¹,

Schöpfer

Baker

et al. 2006

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

120

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Recently, it has been observed that reactions between NO-derived species, unsaturated fatty acids, and lipid oxidation intermediates yield fatty acid oxidation and nitration products (2, 3). Nitroalkene derivatives of all principal unsaturated fatty acids are present in human blood and urine and represent an abundant pool of bioactive oxides of nitrogen, with tissue levels of these species influenced by endogenous redox reactions and dietary intake of nitrated lipids. Nitrolinoleic acid (10-and 12-nitro-9,12-octadecadienoic acid, LNO 2 ) is present in plasma and red blood cell membranes at concentrations of Ϸ500 nM (3). Nitroalkene fatty acid derivatives induce adaptive antiinflammatory responses by means of induction of cGMPdependent and cGMP-independent cell signaling reactions that result in inhibition of platelet and neutrophil activation (4, 5), vessel relaxation (6), and activation of peroxisome proliferatoractivated receptor (PPAR)-dependent gene expression (7).Vascular tissues maintain viability during inflammation by eliciting adaptive and protective responses. Recent studies have shown that heme oxygenase 1 (HO-1) plays a central role in vascular inflammatory signaling reactions and mediates a protective response in several inflammatory diseases, including atherosclerosis, acute renal failure, vascular restenosis, transplant rejection, and sepsis (reviewed in ref. 8). HO-1, a 32-kDa enzyme, is the ratelimiting step in the degradation of heme, yielding biliverdin, carbon monoxide, and iron (9). Biliverdin is subsequently converted to bilirubin by biliverdin reductase. All heme catabolites can contribute to integrative protective responses to oxidative stress (10). Specifically, HO activity reduces levels of prooxidative heme (11), with the iron released from heme catabolism rendered largely redox-inactive by ferritin sequestration. Ferritin is often coinduced with HO-1 and also displays cytoprotective functions (12). Heme degradation serves as the major endogenous source of carbon monoxide, a gas isoelectronic with NO that displays antiinflammatory, antiapoptotic, vasodilatory, and immune modulatory functions (13-15). The porphyrin metabolites biliverdin and bilirubin also scavenge reactive oxygen species (16,17). Finally, HO-1 induction is associated with concomitant up-regulation of the cell-cycle regulatory protein p21, which mediates antiapoptotic signaling during oxidative injury (18). Biliverdin, bilirubin, and carbon monoxide, acting individually or in concert, exert protective effects in vitro and in vivo in animal models of inflammatory injury (19).Because both nitroalkenes and HO-1 are emerging as key mediators of adaptive inflammatory responses, the impact of LNO 2 on HO-1 gene expression was examined. Herein, the marked up-regulation of HO-1 gene expression by LNO 2 in vascular cells is reported, with this induction occurring primarily at the transcriptional level. We conclude that LNO 2 mediates the induction of HO-1 by means of PPAR␥-independent and both NO-dependent and NO-independent mec...

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Section: Discussionmentioning

confidence: 84%

Fatty acid transduction of nitric oxide signaling: Nitrolinoleic acid potently activates endothelial heme oxygenase 1 expression

Wright¹,

Schöpfer

Baker

et al. 2006

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

120

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“…Recently, nitration products of arachidonic acid (27), linoleic acid (38) and cholesteryl linoleate (39) have been reported in biological samples. Importantly, all of these observations were made after lipid extraction of nitrite-containing specimens under No other peaks were detected in the chromatogram.…”

Section: Discussionmentioning

confidence: 99%

Red cell membrane and plasma linoleic acid nitration products: Synthesis, clinical identification, and quantitation

Baker

Schöpfer

Sweeney

et al. 2004

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

192

191

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Nitric oxide ( • NO) and its reactive metabolites mediate the oxidation, nitration, and nitrosation of DNA bases, amino acids, and lipids. Here, we report the structural characterization and quantitation of two allylic nitro derivatives of linoleic acid (LNO 2), present as both free and esterified species in human red cell membranes and plasma lipids. The LNO 2 isomers 10-nitro-9-cis,12-cis-octadecadienoic acid and 12-nitro-9-cis,12-cis-octadecadienoic acid were synthesized and compared with red cell and plasma LNO 2 species based on chromatographic elution and mass spectral properties. Collision-induced dissociation fragmentation patterns from synthetic LNO 2 isomers were identical to those of the two most prevalent LNO 2 positional isomers found in red cells and plasma. By using • NO exerts a particularly broad influence on oxidative inflammatory reactions by reacting at diffusion-limited rates with superoxide ( • O 2 Ϫ , k ϭ 1.9 ϫ 10 10 M Ϫ1 ⅐sec Ϫ1 ) to yield peroxynitrite (ONOO Ϫ ) and its conjugate acid, peroxynitritrous acid (ONOOH), the latter of which undergoes homolytic scission to nitrogen dioxide ( • NO 2 ) and hydroxyl radical ( • OH) (2, 6). Also, biological conditions favor the reaction of ONOO Ϫ with CO 2 , generating nitrosoperoxycarbonate (ONO-OCO 2 Ϫ ; k ϭ 3 ϫ 10 4 M Ϫ1 ⅐sec Ϫ1 ), which yields • NO 2 and carbonate ( • CO 3 Ϫ ) radicals by means of homolysis or rearranges to NO 3 Ϫ and CO 2 (7). During inflammation, neutrophil myeloperoxidase and heme proteins, such as myoglobin and cytochrome c, form H 2 O 2 -dependent Compound I intermediates that are direct oxidants and catalyze the consumption of • NO and the oxidation of nitrite (NO 2 Ϫ ) to • NO 2 (8-11). Although the rate of reaction of • NO with O 2 is slow (k ϭ 2 ϫ 10 6 M Ϫ2 ⅐sec Ϫ1 ), the small molecular radius, uncharged nature, and lipophilicity of • NO and O 2 facilitate their diffusion and concentration in membranes and lipoproteins up to 20-fold (12-14). This ''molecular lens'' effect that is induced by solvation in hydrophobic cell compartments accelerates the reaction of • NO with O 2 to yield N 2 O 3 and N 2 O 4 . As a consequence of this diversity of • NO reactions with partially reduced oxygen species, a rich spectrum of products is formed that orchestrates target molecule oxidation, nitrosation, and nitration reactions.Multiple mechanisms account for the nitration of fatty acids by• NO-derived species (15)(16)(17)(18)(19)(20). During both basal cell-signaling and tissue-inflammatory conditions, • NO 2 that is generated by the aforementioned reactions can react with membrane and lipoprotein lipids. Environmental sources also yield • NO 2 as a product of combustion.• NO 2 initiates autooxidation of polyunsaturated fatty acids by means of hydrogen abstraction from the bis-allylic carbon, to form nitrous acid and a resonance-stabilized allylic radical (21). This lipid radical species predominantly reacts with molecular oxygen to form a peroxyl radical. During the unique oxidationreduction conditions of inflammation or ischemia-...

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“…LAOOH ( Fig. 1) was synthesized in the Sã o Paulo laboratory as described previously (50,51). Hydroxylapatite, Bio-Gel HTP, and Bio-Beads SM2 were from Bio-Rad.…”

Section: Methodsmentioning

confidence: 99%

“…We examined interactions of linoleic acid hydroperoxides (LAOOH) (50,51) with liposomal membranes and with reconstituted UCP2. We found that LAOOH does rapidly flip-flop across the membrane, resulting in the delivery of protons to the interior.…”

mentioning

confidence: 99%

Hydroperoxy Fatty Acid Cycling Mediated by Mitochondrial Uncoupling Protein UCP2

Jabůrek

Miyamoto

Mascio

et al. 2004

Journal of Biological Chemistry

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Using Escherichia coli-expressed UCP2 reconstituted into liposomes we found that LAOOH induced purine nucleotide-sensitive H ؉ uniport in UCP2-proteoliposomes with higher affinity than LA (K m values 97 M for LAOOH and 275 M for LA). In UCP2-proteoliposomes LAOOH also induced purine nucleotide-sensitive K ؉ influx balanced by anionic charge transfer, indicating that LAOOH was also transported as an anion with higher affinity than linoleate anion, the K m values being 90 and 350 M, respectively. These data suggest that hydroperoxy fatty acids are transported via UCP2 by a fatty acid cycling mechanism. This may alternatively explain the observed activation of UCP2 by the externally generated superoxide. The ability of LAOOH to induce UCP2-mediated H ؉ uniport points to the essential role of superoxide reaction products, such as hydroperoxyl radical, hydroxyl radical, or peroxynitrite, initiating lipoperoxidation, the released products of which support the UCP2-mediated uncoupling and promote the feedback down-regulation of mitochondrial reactive oxygen species production.

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Characterization of Linoleic Acid Nitration in Human Blood Plasma by Mass Spectrometry

Cited by 99 publications

References 30 publications

Fatty acid transduction of nitric oxide signaling: Nitrolinoleic acid potently activates endothelial heme oxygenase 1 expression

Fatty acid transduction of nitric oxide signaling: Nitrolinoleic acid potently activates endothelial heme oxygenase 1 expression

Red cell membrane and plasma linoleic acid nitration products: Synthesis, clinical identification, and quantitation

Hydroperoxy Fatty Acid Cycling Mediated by Mitochondrial Uncoupling Protein UCP2

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