Effects of reactive metabolites of oxygen and nitrogen on gelatinase A activity.
The regulation of matrix metalloproteinase activity is crucial for maintaining the proper balance of tissue remodeling vs. injury. Metalloproteinase proenzymes are activated when the active site zinc is exposed via a cysteine switch mechanism. Peroxynitrite, the product generated 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 effects of nitric oxide and superoxide generators on gelatinase A activity. Results showed that nitric oxide alone had no effect on gelatinase A activity relative to control, whereas superoxide-derived metabolites increased activity. The simultaneous generation of both nitric oxide and superoxide caused an inhibition of gelatinase A activity. This inhibition was reversed by the addition of hemoglobin, superoxide dismutase, or sodium urate, suggesting that peroxynitrite and/or peroxynitrous 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 metalloproteinase activity and thus affect matrix protein metabolism.
Owens
M W
MW
Department of Medicine, Overton Brooks Veterans Affairs, Shreveport, Louisiana, USA.
Milligan
S A
SA
Jourd'heuil
D
D
Grisham
M B
MB
D000818:Animals; D004791:Enzyme Inhibitors / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D018093:Gelatinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008168:Lung / Q000166:cytology / Q000378:metabolism; D020778:Matrix Metalloproteinase 2; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009566:Nitrates / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism / Q000502:physiology; D009584:Nitrogen / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism*; D051381:Rats; D013481:Superoxides / Q000378:metabolism
D004791:Enzyme Inhibitors; D009566:Nitrates; D013481:Superoxides; C039642:peroxynitric acid; D009569:Nitric Oxide; D018093:Gelatinases; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D009584:Nitrogen; D010100:Oxygen