Nitrolinoleate Inhibits Superoxide Generation, Degranulation, and Integrin Expression by Human Neutrophils

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Abstract
Nitration of unsaturated fatty acids such as linoleate by NO-derived reactive species forms novel derivatives (including nitrolinoleate [LNO 2 ]) that can stimulate smooth muscle relaxation and block platelet activation by either NO/cGMP or cAMP-dependent mechanisms. Here, LNO 2 was observed to inhibit human neutrophil function. LNO 2 , but not linoleic acid or the nitrated amino acid 3-nitrotyrosine, dose-dependently (0.2 to 1 μmol/L) inhibited superoxide (O 2 ·− ) generation, Ca 2+ influx, elastase release, and CD11b expression in response to either phorbol 12-myristate 13-acetate or N -formyl-Met-Leu-Phe. LNO 2 did not elevate cGMP, and inhibition of guanylate cyclase by 1 H -[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one did not restore neutrophil responses, ruling out a role for NO. In contrast, LNO 2 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 LNO 2 , indicating that LNO 2 may inhibit signaling both upstream and downstream of protein kinase C. These data suggest novel signaling actions for LNO 2 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.