Formation of nitric oxide-derived inflammatory oxidants by myeloperoxidase in neutrophils

Jason P. Eiserich (), Milena Hristova, Carroll E. Cross, A. Daniel Jones, Alan Freeman, Barry Halliwell and Albert van der Vliet
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Jason P. Eiserich: University of California
Milena Hristova: University of California
Carroll E. Cross: University of California
A. Daniel Jones: Facility for Advanced Instrumentation, University of California
Barry Halliwell: University of California
Albert van der Vliet: University of California

Nature, 1998, vol. 391, issue 6665, 393-397

Abstract: Abstract Nitric oxide (˙NO) plays a central role in the pathogenesis of diverse inflammatory and infectious disorders1,2. The toxicity of ˙NO is thought to be engendered, in part, by its reaction with superoxide (O˙−2), yielding the potent oxidant peroxynitrite (ONOO−)3. However, evidence for a role of ONOO− in vivo is based largely upon detection of 3-nitrotyrosine in injured tissues4,5,6,7,8. We have recently demonstrated that nitrite (NO2−), a major end-product of ˙NO metabolism, readily promotes tyrosine nitration through formation of nitryl chloride (NO2Cl) and nitrogen dioxide (˙NO2) by reaction with the inflammatory mediators hypochlorous acid (HOCl) or myeloperoxidase9,10. We now show that activated human polymorphonuclear neutrophils convert NO2− into NO2Cl and ˙NO2 through myeloperoxidase-dependent pathways. Polymorphonuclear neutrophil-mediated nitration and chlorination of tyrosine residues or 4-hydroxyphenylacetic acid is enhanced by addition of NO2− or by fluxes of ˙NO. Addition of 15NO2− led to 15N enrichment of nitrated phenolic substrates, confirming its role in polymorphonuclear neutrophil-mediated nitration reactions. Polymorphonuclear neutrophil-mediated inactivation of endothelial cell angiotensin-converting enzyme was exacerbated by NO2−, illustrating the physiological significance of these reaction pathways to cellular dysfunction. Our data reveal that NO2− may regulate inflammatory processes through oxidative mechanisms, perhaps by contributing to the tyrosine nitration and chlorination observed in vivo.

Date: 1998
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DOI: 10.1038/34923

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