EFFECTS OF REACTIVE METABOLITES OF OXYGEN AND NITROGEN ON GELATINASE-A ACTIVITY

Effects of reactive metabolites of oxygen and nitrogen on gelatinase A activity Am. J. Physiol. 273 (Lung Cell. Mol. Physiol. 17): L445-L450 , 1997.-The regulation of matrix metalloproteinase activity is crucial for maintaining the proper balance of tissue remodeling vs. injury. M etalloproteinase proenzymes are activated when the active site zinc is exposed via a cysteine switch mechanism. Peroxynitrite, the product g enerated from the interaction between nitric oxide and superoxide, has been shown to release zinc from zinc-thiolate groups, suggesting that it might alter metalloproteinase activity. This study examined the ef fects of nitric oxide and superoxide generators on gelatinase A activi ty. Results showed that nitric oxide alone had no effect on gelatinase A activity relative to control, whereas superoxide-derived metabolite s increased activity. The simultaneous generation of both nitric oxide and superoxide caused an inhibition of gelatinase A activity. This in hibition was reversed by the addition of hemoglobin, superoxide dismut ase, or sodium urate, suggesting that peroxynitrite and/or peroxynitro us acid caused the inhibition. Authentic peroxynitrite also inhibited gelatinase A activity. We postulate that the relative fluxes of nitric oxide and superoxide at sites of inflammation may modulate metallopro teinase activity and thus affect matrix protein metabolism.