(The FASEB Journal. 2008;22:lb645)
© 2008 FASEB
Matrix metalloproteinase-2 contributes to hydrogen peroxide induced cardiac myocyte apoptosis
Mohammad Abdel-Motaal Ali,
Miranda Sung,
Thanh Tran,
Bryan Crawford,
Cory Rosenfelt,
Grzegorz Sawicki,
Nanette Bishopric and
Richard Schulz
Pharmacology, University of Alberta, Edmonton, 0, Canada
ABSTRACT
Reperfusion of the ischemic heart triggers the biosynthesis of reactive oxygen species that damage the myocardium and trigger myocyte apoptosis. Matrix metalloproteinase (MMP)-2 is activated during ischemia-reperfusion injury and mediates contractile dysfunction by proteolyzing novel intracellular targets. We hypothesized that MMP-2 may be a mediator of apoptosis by cleaving Bid. Neonatal rat cardiac myocytes were treated with 200 µM H2O2 +/– MMP inhibitors (50 µM o-phenanthroline or 1 nM tissue inhibitor of metalloproteinase-2). H2O2-induced apoptosis was preceded by early permeabilization of the sarcolemma and reduction in mitochondrial membrane potential; with delayed activation of caspase 3 and DNA fragmentation. MMP inhibitors significantly reduced H2O2-induced apoptotic cell death. H2O2 caused an increase in MMP-2 activity in cell lysates. Incubation of Bid with MMP-2 (4 hr, 37°C) resulted in its cleavage and those cleaved fragments induced cytochrome C release from isolated mitochondria, similar to caspase-8 or calpain cleaved Bid. These data suggest that MMP-2 may be a novel mediator of H2O2-induced apoptotic signalling through proteolytic activation of Bid, a pathway that can be abolished by MMP inhibitors.
