US EPA

3074271 

Journal Article 

Nitrite and nitrate-dependent generation of anti-inflammatory fatty acid nitroalkenes 

Delmastro-Greenwood, M; Hughan, KS; Vitturi, DA; Salvatore, , SR; Grimes, G; Potti, G; Shiva, S; Schopfer, FJ; Gladwin, MT; Freeman, BA; Gelhaus Wendell, S 

2015 

Yes 

Free Radical Biology and Medicine
ISSN: 0891-5849
EISSN: 1873-4596 

89 

333-341 

English 

26385079 

10.1016/j.freeradbiomed.2015.07.149 

WOS:000366355800031 

A gap in our understanding of the beneficial systemic responses to dietary constituents nitrate (NO3(-)), nitrite (NO2(-)) and conjugated linoleic acid (cLA) is the identification of the downstream metabolites that mediate their actions. To examine these reactions in a clinical context, investigational drug preparations of (15)N-labeled NO3(-) and NO2(-) were orally administered to healthy humans with and without cLA. Mass spectrometry analysis of plasma and urine indicated that the nitrating species nitrogen dioxide was formed and reacted with the olefinic carbons of unsaturated fatty acids to yield the electrophilic fatty acid, nitro-cLA (NO2-cLA). These species mediate the post-translational modification (PTM) of proteins via reversible Michael addition with nucleophilic amino acids. The PTM of critical target proteins by electrophilic lipids has been described as a sensing mechanism that regulates adaptive cellular responses, but little is known about the endogenous generation of fatty acid nitroalkenes and their metabolites. We report that healthy humans consuming (15)N-labeled NO3(-) or NO2(-), with and without cLA supplementation, produce (15)NO2-cLA and corresponding metabolites that are detected in plasma and urine. These data support that the dietary constituents NO3(-), NO2(-) and cLA promote the further generation of secondary electrophilic lipid products that are absorbed into the circulation at concentrations sufficient to exert systemic effects before being catabolized or excreted. 

Nitrogen metabolism; Diet; Redox signaling; Nitro-fatty acid; Conjugated linoleic acid; Nitrate; Nitrite