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Matrix metalloproteinase-2 (MMP-2) has emerged as a key protease in various pathologies associated with oxidative stress, including myocardial ischemia-reperfusion, heart failure or inflammation. Peroxynitrite (ONOO—), an important effector of oxidative stress, was reported to activate some full length MMP zymogens, particularly in the presence of glutathione (GSH), but whether this occurs for MMP-2 is unknown. Treating MMP-2 zymogen with ONOO— resulted in a concentration-dependent regulation of MMP-2, with 0.3-1 μM ONOO— increasing and 30-100 μM ONOO— attenuating enzyme activity. The enzyme's Vmax was also significantly increased by 1 μM ONOO—. Comparable responses to ONOO— treatment were observed using the intracellular target of MMP-2, troponin I (TnI). GSH at 100 μM attenuated the effects of ONOO— on MMP-2. Mass spectrometry revealed that ONOO— can oxidize and, in the presence of GSH, S-glutathiolate the MMP-2 zymogen or a synthetic peptide containing the cysteine-switch motif in the enzyme's autoinhibitory domain. These results suggest that ONOO— and GSH can modulate the activity of 72 kDa MMP-2 by modifying the cysteine residue in the autoinhibitory domain of the zymogen, a process that may be relevant to pathophysiological conditions associated with increased oxidative stress.