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Matrix metalloproteinase‐2 contributes to hydrogen peroxide induced cardiac myocyte apoptosis
Author(s) -
Ali Mohammad AbdelMotaal,
Sung Miranda,
Tran Thanh,
Crawford Bryan,
Rosenfelt Cory,
Sawicki Grzegorz,
Bishopric Nanette,
Schulz Richard
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.2_supplement.645
Subject(s) - matrix metalloproteinase , apoptosis , microbiology and biotechnology , chemistry , myocyte , cytochrome c , reactive oxygen species , calpain , intracellular , caspase , programmed cell death , biology , biochemistry , enzyme
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 H 2 O 2 +/− MMP inhibitors (50 μM o‐phenanthroline or 1 nM tissue inhibitor of metalloproteinase‐2). H 2 O 2 ‐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 H 2 O 2 ‐induced apoptotic cell death. H 2 O 2 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 H 2 O 2 ‐induced apoptotic signalling through proteolytic activation of Bid, a pathway that can be abolished by MMP inhibitors.