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Center of Vascular Biology, Weill Medical College of Cornell University, 1300 York Avenue, New York, New York 10021
2 To whom correspondence should be addressed. e-mail: rupmacis{at}med.cornell.edu
In this study, we investigated the effects of various nitrogen oxide (NOx) species on the extent of prostaglandin H2 synthase-1 (PGHS-1) nitration in purified protein and in vascular smooth muscle cells. We also examined PGHS-1 activity under these conditions and found the degree of nitration to correlate inversely with enzyme activity. In addition, since NOx species are thought to invoke damage during the pathogenesis of atherosclerosis, we examined human atheromatous tissue for PGHS-1 nitration. Both peroxynitrite and tetranitromethane induced Tyr nitration of purified PGHS-1, whereas 1-hydroxy-2-oxo-3-(N-methyl-aminopropyl)-3-methyl-1-triazene (NOC-7; a nitric oxide-releasing compound) did not. Smooth muscle cells treated with peroxynitrite showed PGHS-1 nitration. The extent of nitration by specific NOx species was determined by electrospray ionization mass spectrometry. Tetranitromethane was more effective than peroxynitrite, NOC-7, and nitrogen dioxide at nitrating a tyrosine-containing peptide (12%, 5%, 1%, and <1% nitration, respectively). Nitrogen dioxide and, to a lesser extent, peroxynitrite, induced dityrosine formation. Using UV/Vis spectroscopy, it was estimated that the reaction of PGHS-1 with excess peroxynitrite yielded two nitrated tyrosines/PGHS-1 subunit. Finally, atherosclerotic tissue obtained from endarterectomy patients was shown to contain nitrated PGHS-1.
Thus, prolonged exposure to elevated levels of peroxynitrite may cause oxidative damage through tyrosine nitration.
Abbreviations: NOx, nitrogen oxides; NOC-7, 1-hydroxy-2-oxo-3-(N-methyl-aminopropyl)-3-methyl-1-triazene; PGHS-1, prostaglandin H2 synthase-1; PGHS-2, prostaglandin H2 synthase-2; SIN-1, 3-morpholinosydnonimine hydrochloride; TNM, tetranitromethane
Supplementary key words peroxynitrite • atherosclerosis • cyclooxygenase
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