title: Hydrogen peroxide-induced necrotic cell death in cardiomyocytes is independent of matrix metalloproteinase-2.
abstract: Matrix metalloproteinase-2 (MMP-2) is well known to proteolyse both extracellular and intracellular proteins. Reactive oxygen species activate MMP-2 at both transcriptional and post-translational levels, thus MMP-2 activation is considered an early event in oxidative stress injury. Although hydrogen peroxide is widely used to trigger oxidative stress-induced cell death, the type of cell death (apoptosis vs. necrosis) in cardiomyocytes is still controversial depending on the concentration used and the exposure time. We carefully investigated the mode of cell death in neonatal rat cardiomyocytes induced by different concentrations (50-500 μM) of hydrogen peroxide at various time intervals after exposure and determined whether MMP-2 is implicated in hydrogen peroxide-induced cardiomyocyte death. Treating cardiomyocytes with hydrogen peroxide led to elevated MMP-2 level/activity with maximal effects seen at 200 μM. Hydrogen peroxide caused necrotic cell death by disrupting the plasmalemma as evidenced by the release of lactate dehydrogenase in a concentration- and time-dependent manner as well as the necrotic cleavage of PARP-1. The absence of both caspase-3 cleavage/activation and apoptotic cleavage of PARP-1 illustrated the weak contribution of apoptosis. Pre-treatment with selective MMP inhibitors did not protect against hydrogen peroxide-induced necrosis. In conclusion hydrogen peroxide increases MMP-2 level/activity in cardiomyocytes and induces necrotic cell death, however, the later effect is MMP-2 independent.
authors.affiliation: Department of Pharmacology, Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Mohammad A M
authors.initials: MA
authors.lastname: Ali
authors.forename: Arulmozhi D
authors.initials: AD
authors.lastname: Kandasamy
authors.forename: Xiaohu
authors.initials: X
authors.lastname: Fan
authors.forename: Richard
authors.initials: R
authors.lastname: Schulz
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D006861:Hydrogen Peroxide / Q000633:toxicity*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D009336:Necrosis / Q000139:chemically induced; D016877:Oxidants / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D016877:Oxidants; D006861:Hydrogen Peroxide; D053148:Caspase 3; D020778:Matrix Metalloproteinase 2; C522363:Mmp2 protein, rat
keywords: Apoptosis; Cardiomyocyte; Hydrogen peroxide; MMP; Matrix metalloproteinase; Matrix metalloproteinase-2; Necrosis