Article ID Journal Published Year Pages File Type
1911448 Free Radical Biology and Medicine 2007 12 Pages PDF
Abstract

The oxidant peroxynitrite/peroxynitrous acid (ONOO−/ONOOH) is generated at sites of inflammation via reaction of O2− with NO. Previous studies have shown that these species can oxidize cellular targets, but few data are available on damage to extracellular matrix and its components, despite evidence for matrix modification in a number of pathologies. In the current study we show that reaction of ONOO−/ONOOH with glycosaminoglycans results in extensive polymer fragmentation. Bolus authentic ONOO−/ONOOH modifies hyaluronan, heparin, and chondroitin, dermatan, and heparan sulfates, in a concentration-dependent, but O2-independent, manner. The ONOO−/ONOOH generator 3-(4-morpholinyl)sydnoneimine produces similar time- and concentration-dependent damage. These reactions generate specific polymer fragments via cleavage at disaccharide intervals. Studies at different pH values, and in the presence of bicarbonate, are consistent with ONOOH, rather than the carbonate adduct, CO3− or ONOO−, being the source of damage. EPR spin trapping experiments have provided evidence for the formation of carbon-centered radicals on glycosaminoglycans and related monosaccharides; the similarity of these spectra to those obtained with authentic HO is consistent with fragmentation being induced by this oxidant. These data suggest that extracellular matrix fragmentation at sites of inflammation may be due, in part, to the formation and reactions of ONOOH.

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