Nitrolinoleate Inhibits Superoxide Generation, Degranulation, and Integrin Expression by Human Neutrophils: Novel Antiinflammatory Properties of Nitric Oxide-Derived Reactive Species in Vascular Cells

• Published in: Circulation research Vol. 91; no. 5; pp. 375 - 381
• Main Authors: Coles, Barbara, Bloodsworth, Allison, Clark, Stephen R, Lewis, Malcolm J, Cross, Andrew R, Freeman, Bruce A, O’Donnell, Valerie B
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 06.09.2002; Lippincott; Lippincott Williams & Wilkins Ovid Technologies
• Subjects: 1-Methyl-3-isobutylxanthine - pharmacology; Anti-Inflammatory Agents - pharmacology; Biological and medical sciences; Calcium - metabolism; Cardiology. Vascular system; Cell Degranulation - drug effects; Cyclic AMP - metabolism; Cyclic GMP - metabolism; Dose-Response Relationship, Drug; Heart; Heart failure, cardiogenic pulmonary edema, cardiac enlargement; Humans; Integrins - biosynthesis; Integrins - drug effects; Linoleic Acid - chemistry; Linoleic Acid - pharmacology; Medical sciences; N-Formylmethionine Leucyl-Phenylalanine - pharmacology; NADPH Oxidases - metabolism; Neutrophils - drug effects; Neutrophils - metabolism; Neutrophils - physiology; Nitro Compounds - chemistry; Nitro Compounds - pharmacology; Phosphodiesterase Inhibitors - pharmacology; Superoxides - metabolism; Tetradecanoylphorbol Acetate - pharmacology; Human; Nitration; Pathogenesis; Antiinflammatory agent; Cardiovascular disease; Lipids; Biosynthesis; Inflammation; Gene expression; Biological activity; Vascular disease; Prevention; Integrin; Nitric oxide; Atherosclerosis; Degranulation; Inhibition; Neutrophil
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/01.RES.0000032114.68919.EF

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 μmol/L) inhibited superoxide (O2) generation, Ca 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 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, 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.