title: Nitrolinoleate inhibits superoxide generation, degranulation, and integrin expression by human neutrophils: novel antiinflammatory properties of nitric oxide-derived reactive species in vascular cells.
abstract: Nitration of unsaturated fatty acids such as linoleate by NO-derived reactive species forms novel derivatives (including nitrolinoleate [LNO2]) that can stimulate smooth muscle relaxation and block platelet activation by either NO/cGMP or cAMP-dependent mechanisms. Here, LNO2 was observed to inhibit human neutrophil function. LNO2, but not linoleic acid or the nitrated amino acid 3-nitrotyrosine, dose-dependently (0.2 to 1 micromol/L) inhibited superoxide (O2*-) generation, Ca2+ influx, elastase release, and CD11b expression in response to either phorbol 12-myristate 13-acetate or N-formyl-Met-Leu-Phe. LNO2 did not elevate cGMP, and inhibition of guanylate cyclase by 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one did not restore neutrophil responses, ruling out a role for NO. In contrast, LNO2 caused elevations in intracellular cAMP in the presence and absence of phosphodiesterase inhibition, suggesting activation of adenylate cyclase. Compared with phorbol 12-myristate 13-acetate-activated neutrophils, N-formyl-Met-Leu-Phe-activated neutrophils were more susceptible to the inhibitory effects of LNO2, indicating that LNO2 may inhibit signaling both upstream and downstream of protein kinase C. These data suggest novel signaling actions for LNO2 in mediating its potent inhibitory actions. Thus, nitration of lipids by NO-derived reactive species yields products with antiinflammatory properties, revealing a novel mechanism by which NO-derived nitrated biomolecules can influence the progression of vascular disease.
authors.affiliation: Department of Medical Biochemistry, University of Wales College of Medicine, Cardiff, UK.
authors.forename: Barbara
authors.initials: B
authors.lastname: Coles
authors.forename: Allison
authors.initials: A
authors.lastname: Bloodsworth
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Clark
authors.forename: Malcolm J
authors.initials: MJ
authors.lastname: Lewis
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Cross
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Freeman
authors.forename: Valerie B
authors.initials: VB
authors.lastname: O'Donnell
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D015550:Cell Degranulation / Q000187:drug effects*; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D016023:Integrins / Q000096:biosynthesis / Q000187:drug effects*; D019787:Linoleic Acid / Q000737:chemistry / Q000494:pharmacology*; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D019255:NADPH Oxidases / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D009574:Nitro Compounds / Q000737:chemistry / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
chemical_list: D000893:Anti-Inflammatory Agents; D016023:Integrins; D009574:Nitro Compounds; D010726:Phosphodiesterase Inhibitors; D013481:Superoxides; D009240:N-Formylmethionine Leucyl-Phenylalanine; D019787:Linoleic Acid; D000242:Cyclic AMP; D019255:NADPH Oxidases; D006152:Cyclic GMP; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium; D015056:1-Methyl-3-isobutylxanthine