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(Circulation Research. 2002;91:375.)
© 2002 American Heart Association, Inc.

Molecular Medicine

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

Novel Antiinflammatory Properties of Nitric Oxide–Derived Reactive Species in Vascular Cells

Barbara Coles, Allison Bloodsworth, Stephen R. Clark, Malcolm J. Lewis, Andrew R. Cross, Bruce A. Freeman, Valerie B. O’Donnell

From the Department of Medical Biochemistry (B.C., S.R.C., V.B.O.) and the Department of Pharmacology, Therapeutics, and Toxicology (M.J.L.), University of Wales College of Medicine, Cardiff, UK; the Department of Molecular and Experimental Medicine (A.R.C.), The Scripps Research Institute, La Jolla, Calif; and the Departments of Anesthesiology, Biochemistry, and Molecular Genetics and the Center for Free Radical Biology (A.B., B.A.F.), University of Alabama at Birmingham.

Correspondence to Valerie O’Donnell, PhD, Wellcome Trust RCD Lecturer, Department of Medical Biochemistry, University of Wales College of Medicine, Heath Park, Cardiff CF4 4XN, UK. E-mail o-donnellvb{at}cf.ac.uk

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 µmol/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.

Key Words: nitric oxide • nitrolinoleate • neutrophils • atherosclerosis • peroxynitrite

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