INACTIVATION OF TISSUE INHIBITOR OF METALLOPROTEINASE-1 BY PEROXYNITRITE

Peroxynitrite (ONOO-) has recently been implicated in connective tissu e destruction in vivo, We have studied the effect of ONOO- on the acti vity of tissue inhibitor of metalloproteinase-1 (TIMP-1) in vitro, The inactivation of TIMP-1 by ONOO- was dose dependent with 50 mu M ONOO- reducing the inhibitory activity of TIMP-1 towards gelatinase-A by 50 %. High concentrations of ONOO- (500 mu M-5 mM) caused protein fragmen tation whilst lower concentrations (< 250 mu M) inactivated TIMP-1 wit hout altering the molecular weight, Inactivation could be blocked by O NOO- scavengers but not by hydroxyl radical scavengers, Our results sh ow that ONOO- is capable of inactivating TIMP-1, a process which could potentiate metalloproteinase-mediated tissue breakdown.