Nitrated lipids decompose to nitric oxide and lipid radicals and cause vasorelaxation

Lima, Emerson Silva; Bonini, Marcelo G.; Augusto, Ohára; Barbeiro, Hermes Vieira; Souza, Heraldo Possolo de; Abdalla, Dulcinéia Saes Parra

doi:10.1016/j.freeradbiomed.2005.04.005

Cited by 126 publications

(84 citation statements)

References 31 publications

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“…These findings are rational as the KI was specifically engineered to lack Cys521 to be resistant to such electrophiles. It is controversial as to whether lipid nitroalkenes induce vessel relaxation in biological milieu via release of NO (32,33). Herein, NO 2 -OA-induced vasorelaxation was unaffected by inhibition of soluble guanylate cyclase, the major target of NO.…”

Section: Discussionmentioning

confidence: 91%

Protection from hypertension in mice by the Mediterranean diet is mediated by nitro fatty acid inhibition of soluble epoxide hydrolase

Charles

Rudyk

Prysyazhna

et al. 2014

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

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Soluble epoxide hydrolase (sEH) is inhibited by electrophilic lipids by their adduction to Cys521 proximal to its catalytic center. This inhibition prevents hydrolysis of the enzymes' epoxyeicosatrienoic acid (EET) substrates, so they accumulate inducing vasodilation to lower blood pressure (BP). We generated a Cys521Ser sEH redoxdead knockin (KI) mouse model that was resistant to this mode of inhibition. The electrophilic lipid 10-nitro-oleic acid (NO 2 -OA) inhibited hydrolase activity and also lowered BP in an angiotensin II-induced hypertension model in wild-type (WT) but not KI mice. Furthermore, EET/dihydroxy-epoxyeicosatrienoic acid isomer ratios were elevated in plasma from WT but not KI mice following NO 2 -OA treatment, consistent with the redox-dead mutant being resistant to inhibition by lipid electrophiles. sEH was inhibited in WT mice fed linoleic acid and nitrite, key constituents of the Mediterranean diet that elevates electrophilic nitro fatty acid levels, whereas KIs were unaffected. These observations reveal that lipid electrophiles such as NO 2 -OA mediate antihypertensive signaling actions by inhibiting sEH and suggest a mechanism accounting for protection from hypertension afforded by the Mediterranean diet.thiol | cardiovascular

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Section: Discussionmentioning

confidence: 91%

Protection from hypertension in mice by the Mediterranean diet is mediated by nitro fatty acid inhibition of soluble epoxide hydrolase

Charles

Rudyk

Prysyazhna

et al. 2014

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

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“…As mentioned previously, the generation of · NO 2 from the reaction of · NO and O 2 is much more probable in membranes compared to the aqueous cytosol due to the partitioning of these species into hydrophobic environments (108). The release of · NO from nitrated lipids has been examined and several mechanisms have been proposed involving homolytic cleavage of a precursor to generate · NO and a relatively stable radical co-product (132,133). Regardless, the biological activity associated with nitrolipids is another example of the close relationship between · NO and O 2 signaling/biology since both species are required for the generation of nitrolipids, a process that is greatly enhanced by their abilities to favorably partition into membranes.…”

Section: B Fatty Acid Nitrationmentioning

confidence: 99%

The chemistry of cell signaling by reactive oxygen and nitrogen species and 4-hydroxynonenal

Forman

Fukuto

Miller

et al. 2008

Archives of Biochemistry and Biophysics

217

165

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During the past several years, major advances have been made in understanding how reactive oxygen species (ROS) and nitrogen species (RNS) participate in signal transduction. Identification of the specific targets and the chemical reactions involved still remains to be resolved with many of the signaling pathways in which the involvement of reactive species has been determined. Our understanding is that ROS and RNS have second messenger roles. While cysteine residues in the thiolate (ionized) form found in several classes of signaling proteins can be specific targets for reaction with H 2 O 2 and RNS, better understanding of the chemistry, particularly kinetics, suggests that for many signaling events in which ROS and RNS participate, enzymatic catalysis is more likely to be involved than non-enzymatic reaction. Due to increased interest in how oxidation products, particularly lipid peroxidation products, also are involved with signaling, a review of signaling by 4-hydroxy-2-nonenal (HNE) is included. This article focuses on the chemistry of signaling by ROS, RNS, and HNE and will describe reactions with selected target proteins as representatives of the mechanisms rather attempt to comprehensively review the many signaling pathways in which the reactive species are involved. Keywords signaling; glutathione; thioredoxin; oxidants; reactive oxygen species; thiols; peroxide; nitric oxide; peroxynitrite; 4-hydroxynonenal; cysteine; hydrogen peroxide; protein tyrosine phosphatase; reactive nitrogen species; eNOS; iNOS; nNOS; soluble guanylate cyclase; cGMP; tyrosine nitration; fatty acid nitration; NO-heme; NO-metal complexes; nitrite; protein kinase C; ERK; JNK; p38MAPK; tyrosine kinase receptors; calcium OVERVIEW OF SIGNALING BY REACTIVE SPECIESUnderstanding of the roles of reactive oxygen species (ROS), reactive nitrogen species (RNS) and the lipid peroxidation product, 4-hydroxy-2-nonenal (HNE) in signaling has evolved rapidly during the last decade. This has been markedly helped by identification of the specific targets in signaling pathways. In previous reviews, we defined how ROS, H 2 O 2 in particular,

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“…12-LNO 2 was synthesized and purified as described previously. 8 Specifically, the purity of the 12-LNO 2 used in this study was Ն98%, which was determined by mass spectrometry. 9-OA-NO 2 , spermine-NONOate (sper/NO), diethylenetriamine-NONOate (deta/NO), and 1H- [1,2,4]oxadiazolo [4,3-a]quinoxalin-1-one were purchased from Cayman Chemicals.…”

Section: Reagentsmentioning

confidence: 99%

“…Taken together, these results support the concept of NO release from NO 2 -FAs, which in turn promotes angiogenesis in ECs. In fact, recent data 4,7,8,32 pointed out that LNO 2 and OA-NO 2 act as direct reservoirs for NO 4,8 and release NO via a Nef reaction. 7 Regardless of the mechanism involved in the increase in bioavailable NO in response to NO 2 -FAs, our data suggest that both stabilization and activation of HIF-1 are required to 34 However, we cannot rule out the possibility that NO 2 -FA-induced heme oxygenase-1 expression may also be occurring and that this could also promote angiogenesis.…”

mentioning

confidence: 99%

“…5 NO 2 -FAs also activate the peroxisome proliferator-activated receptor-␥ 6 and might mediate reversible posttranslational protein modifications through nitroalkylation reactions both with low-molecularweight thiols and with cysteine and histidine residues of proteins. 2 Furthermore, NO 2 -FAs not only serve as reservoirs for NO but also may act as endogenous NO donors, 4,7 inducing vessel relaxation 8,9 and upregulating endothelial NO synthase expression and activity, ultimately increasing NO levels. 10 NO is a well-established modulator of angiogenesis, 11 which is a crucial process during embryonic development and in several pathological conditions, including vascular diseases.…”

mentioning

confidence: 99%

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Hypoxia Inducible Factor–Dependent Regulation of Angiogenesis by Nitro–Fatty Acids

Rudnicki

Faine

Dehne

et al. 2011

ATVB

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Objective-Nitro-fatty acids (NO 2 -FAs) are emerging as a new class of cell signaling mediators. Because NO 2 -FAs are found in the vascular compartment and their impact on vascularization remains unknown, we aimed to investigate the role of NO 2 -FAs in angiogenesis. Methods and Results-The effects of nitrolinoleic acid and nitrooleic acid were evaluated on migration of endothelial cell (EC) in vitro, EC sprouting ex vivo, and angiogenesis in the chorioallantoic membrane assay in vivo. At 10 mol/L, both NO 2 -FAs induced EC migration and the formation of sprouts and promoted angiogenesis in vivo in an NO-dependent manner. In addition, NO 2 -FAs increased intracellular NO concentration, upregulated protein expression of the hypoxia inducible factor-1␣ (HIF-1␣) transcription factor by an NO-mediated mechanism, and induced expression of HIF-1␣ target genes, such as vascular endothelial growth factor, glucose transporter-1, and adrenomedullin. Compared with typical NO donors such as spermine-NONOate and deta-NONOate, NO 2 -FAs were slightly less potent inducers of EC migration and HIF-1␣ expression. Short hairpin RNA-mediated knockdown of HIF-1␣ attenuated the induction of vascular endothelial growth factor mRNA expression and EC migration stimulated by NO 2 -FAs. Conclusion-Our data disclose a novel physiological role for NO 2 -FAs, indicating that these compounds induce angiogenesis in an NO-dependent mechanism via activation of HIF-1␣. Key Words: angiogenesis Ⅲ nitric oxide Ⅲ hypoxia inducible factor-1 Ⅲ nitro-fatty acids N itro-fatty acids (NO 2 -FAs) are nitroalkene products of polyunsaturated fatty acids, nitrated by nitric oxide (NO)-derived species. 1 NO 2 -FAs, including nitrolinoleic acid (LNO 2 ) and nitrooleic acid (OA-NO 2 ), have pluripotent cell signaling capabilities. For example, they exhibit antiinflammatory properties by inhibiting platelet aggregation and neutrophil activation 2 and upregulating heme oxygenase-1 expression. 3 Recently, the ability to nitrosate CD40 4 and potential cardioprotective effects have also been ascribed to these compounds. 5 Interestingly, OA-NO 2 was found in reperfused ischemic heart tissue, indicating that its formation might occur during the reperfusion process. Moreover, exogenous administration of OA-NO 2 also mitigates the damage induced by tissue reoxygenation. 5 NO 2 -FAs also activate the peroxisome proliferator-activated receptor-␥ 6 and might mediate reversible posttranslational protein modifications through nitroalkylation reactions both with low-molecularweight thiols and with cysteine and histidine residues of proteins. 2 Furthermore, NO 2 -FAs not only serve as reservoirs for NO but also may act as endogenous NO donors,4,7 inducing vessel relaxation 8,9 and upregulating endothelial NO synthase expression and activity, ultimately increasing NO levels. 10 NO is a well-established modulator of angiogenesis, 11 which is a crucial process during embryonic development and in several pathological conditions, including vascular diseases. 12 Angiogenesis is tight...

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Nitrated lipids decompose to nitric oxide and lipid radicals and cause vasorelaxation

Cited by 126 publications

References 31 publications

Protection from hypertension in mice by the Mediterranean diet is mediated by nitro fatty acid inhibition of soluble epoxide hydrolase

Protection from hypertension in mice by the Mediterranean diet is mediated by nitro fatty acid inhibition of soluble epoxide hydrolase

The chemistry of cell signaling by reactive oxygen and nitrogen species and 4-hydroxynonenal

Hypoxia Inducible Factor–Dependent Regulation of Angiogenesis by Nitro–Fatty Acids

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