Activation of Peroxisome Proliferator-Activated Receptor γ (PPARγ) by Nitroalkene Fatty Acids: Importance of Nitration Position and Degree of Unsaturation

Gorczynski, Michael J.; Smitherman, Pamela K.; Akiyama, Taro E.; Wood, Harold B.; Berger, Joel P.; King, S. Bruce; Morrow, Charles S.

doi:10.1021/jm900326c

Cited by 32 publications

(31 citation statements)

References 29 publications

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“…Also, xanthine oxidoreductase activity is inhibited by 9-OA-NO 2 and the mixture of 9-and 10-OA-NO 2 , but not by other structural variants of OA-NO 2 that differ in the nitroalkenyl and carboxylic acid moieties (3). Moreover, the extent of PPAR␥ activation is different by the four nitroalkenyl regioisomers of linoleic acid (9-, 10-, 12-, or 13-nitro-ocatadeca-9,12-dienoic acid) (44). These data underscore the notion that even small changes in nitroalkene fatty acid structure can impact on biological signaling actions.…”

Section: Discussionmentioning

confidence: 98%

Electrophilic Nitro-fatty Acids Activate NRF2 by a KEAP1 Cysteine 151-independent Mechanism

Kansanen

Bonacci

Schöpfer

et al. 2011

Journal of Biological Chemistry

182

184

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Nitro-fatty acids (NOIn this study, we investigate the molecular mechanisms by which 9-and 10-nitro-octadec-9-enoic acid (OA-NO 2 ) activate the transcription factor Nrf2, focusing on the post-translational modifications of cysteines in the Nrf2 inhibitor Keap1 by nitroalkylation and its downstream responses. Of the two regioisomers, 9-nitrooctadec-9-enoic acid was a more potent ARE inducer than 10-nitro-octadec-9-enoic acid. (2), the enzyme xanthine oxidoreductase (3), and the transcription factor peroxisome proliferator-activated receptor ␥ (PPAR␥) (4). Moreover, NO 2 -FAs activate heat shock (5) and antioxidant response pathways (5, 6) via mechanisms that remain to be defined. Antioxidant response element (ARE)-regulated genes play an essential role in the protection against endogenous and exogenous stresses (7). The transcription factor nuclear factor E2-related factor-2 (Nrf2) can activate these genes via binding to AREs as a heterodimer with small Maf proteins (7). Under basal conditions, Nrf2 is bound to its inhibitor Kelch-like ECHassociated protein 1 (Keap1), which functions as an adaptor molecule in the Cul3-based E3 ligase complex. Nrf2 is then rapidly ubiquitinated and degraded (8, 9). During periods when cellular concentrations of oxidative or electrophilic species are elevated, the interaction of Nrf2 with the ubiquitin ligase complex is disrupted, enabling the escape of Nrf2 from degradation, its nuclear translocation, and transactivation of target genes.Keap1 is a Cys-rich protein with 27 Cys residues in the human and 25 Cys residues in the murine protein. Keap1 has four functional domains: the Bric-a-Brac, tramtrack, broad complex (BTB) domain, the intervening region (IVR), the Kelch domain (also known as the double glycine repeat), and the C-terminal region. Alkylation or oxidation of Keap1 Cys residues, predominantly within the IVR, leads to the inactivation of Keap1 and is the central mechanism for the activation of Nrf2 (10 -12). A number of studies utilizing mass spectrometry (MS) analysis show that electrophilic inducers of Nrf2 modify several different Cys residues in recombinant Keap1. These data indi-* This work was supported, in whole or in part, by National Institutes of Health BTB, Bric-a-Brac, tramtrack, broad complex; IVR, intervening region; 15d-PGJ 2 , 15-deoxy-⌬12,14-prostaglandin J 2 ; HEK, human embryonic kidney; ␤-ME, ␤-mercaptoethanol; OA-NO 2 , 9-and 10-nitro-octadec-9-enoic acid; 9-OA-NO 2 , 9-nitro-octadec-9-enoic acid; 10-OA-NO 2 , 10-nitro-octadec-9-enoic acid; LNO 2 , 9-, 10-, 12-, or 13-nitro-octadeca-9,12-dienoic acid.

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Section: Discussionmentioning

confidence: 98%

Electrophilic Nitro-fatty Acids Activate NRF2 by a KEAP1 Cysteine 151-independent Mechanism

Kansanen

Bonacci

Schöpfer

et al. 2011

Journal of Biological Chemistry

182

184

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“…The consideration of plasma and urinary endogenous fatty acid nitroalkenes is relevant beyond a role as biomarkers of oxidative nitration reactions, because these species also potently mediate signaling reactions that limit infl ammation. Potential mechanisms underlying these actions include a ) inhibition of neutrophil function and platelet activation ( 43,44 ), b ) serving as partial agonists for PPAR ␥ ( 14,15,(45)(46)(47), c ) inhibition of cytokine expression via inhibition of DNA binding by the p65 unit of NF-B ( 48 ), and d ) upregulation of phase 2 gene expression via Keap1/Nrf2-dependent ( 5,49,50 ) and -independent mechanisms ( 51 ). Critical pro-infl ammatory enzymatic activities are also inhibited by fatty acid nitroalkenes, including xanthine oxidoreductase and cyclooxygenase-2 ( 52,53 ).…”

Section: Discussionmentioning

confidence: 99%

Characterization and quantification of endogenous fatty acid nitroalkene metabolites in human urine

Salvatore

Vitturi

Baker

et al. 2013

Journal of Lipid Research

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This article is available online at http://www.jlr.org biomolecule nitration ( 1 ). Nitroalkene substituents are electrophilic and promote Michael addition of fatty acids with biological nucleophiles such as cysteine and histidine. The extent, rate, and reversibility of these reactions will be dictated both by the concentration and reactivity of individual nucleophiles. In this regard, protein structure and compartmentalization affect the reactivity of individual nucleophilic centers and will defi ne the molecular targets of electrophilic fatty acids.While enzymatically-oxygenated unsaturated fatty acids typically transduce anti-infl ammatory actions via specifi c g protein-coupled receptor ligand activity ( 2, 3 ), transcriptional responses to electrophilic fatty acids reveal that a broader array of signaling events are instigated ( 4, 5 ). The basis for this pleiotropy resides in the facile Michael addition of electrophilic fatty acid derivatives with nucleophilic centers of proteins that regulate structure and function ( 6 ). Functionally-signifi cant protein targets of electrophilic fatty acids include the transcriptional regulatory protein complex nuclear factor kappa B (NFkB), the

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“…In this context, it is noted that the serum OA-NO 2 levels measured upon chronic in vivo administration are not fully representative of the bioactive species that can accumulate. Electrophilic nitro-fatty acids undergo protein adduction and partial β-oxidation to shorter chain metabolites that can retain signaling capabilities28. Thus the higher concentrations of OA-NO 2 required for inhibition of smooth muscle cell proliferation in vitro may be a reflection of differences in model systems.…”

Section: Discussionmentioning

confidence: 99%

Nitro-Fatty Acid Inhibition of Neointima Formation After Endoluminal Vessel Injury

Cole

Rudolph²,

Khoo

et al. 2009

Circulation Research

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Key Words: fatty acids Ⅲ arteries Ⅲ stenosis Ⅲ nitric oxide B asal and inflammatory redox signaling reactions are broadly regulated by NO. For example, secondary reactions of NO, promoted by a prooxidative inflammatory milieu, yield oxidizing, nitrosating and nitrating species that transduce NO signaling via cGMP-independent and -dependent mechanisms. Nitro-fatty acid (NO 2 -FA) derivatives are 1 class of lipid oxidation byproducts generated by NO-mediated inflammatory reactions. 1 Existing insight indicates that the robust and reversible electrophilic reactivity of NO 2 -FA supports posttranslational protein modifications and transcriptional activation reactions that promote the resolution of inflammation. 2,3 In this regard, in vitro studies reveal NO 2 -FA inhibit platelet aggregation, neutrophil activation, nuclear factor B-mediated cytokine release and stimulate heme oxygenase (HO)-1 expression, all via cGMP-independent mechanisms. 4,5 NO 2 -FA also serve as ligands for peroxisome proliferator-activated receptor ␥, a nuclear lipid receptor that regulates the expression of cell differentiation, development, and inflammatory-related genes. 5,6 In the context of vascular responses to inflammation, NO 2 -FA in part inhibit vascular smooth muscle cell proliferation via activation of the Nrf2 (nuclear factor erythroid 2-related factor 2)/Keap 1 (Kelch-like ECH-associating protein) pathway. 7 Under basal conditions, Keap1 represses nuclear translocation of Nrf2 and Nrf2-dependent transcription. When cells are exposed to reactive species, including thiol-reactive electrophiles such as NO 2 -FA, Nrf2 escapes Keap1-mediated repression to activate antioxidant responsive element-regulated gene expression. 8 Expression of ARE-dependent gene products, including HO-1, 9,10 attenuates inflammatory responses and maintains cellular redox homeostasis.

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Activation of Peroxisome Proliferator-Activated Receptor γ (PPARγ) by Nitroalkene Fatty Acids: Importance of Nitration Position and Degree of Unsaturation

Cited by 32 publications

References 29 publications

Electrophilic Nitro-fatty Acids Activate NRF2 by a KEAP1 Cysteine 151-independent Mechanism

Electrophilic Nitro-fatty Acids Activate NRF2 by a KEAP1 Cysteine 151-independent Mechanism

Characterization and quantification of endogenous fatty acid nitroalkene metabolites in human urine

Nitro-Fatty Acid Inhibition of Neointima Formation After Endoluminal Vessel Injury

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