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Vol. 298, Issue 2, 461-468, August 2001
Departments of Medicine (G.W.W., J.B.K., Y.J.K.) and Pharmacology
and Toxicology (Y.J.K.), University of Louisville, Louisville,
Kentucky; Veterans Affairs Medical Center (J.B.K.), Louisville,
Kentucky; and Jewish Hospital Heart and Lung Institute (Y.J.K.),
Louisville, Kentucky
Previous studies using transgenic mice in which metallothionein
(MT) was overexpressed only in the heart have demonstrated that MT
protects from oxidative cardiac injury induced by doxorubicin (DOX), an
important anticancer agent. MT cardioprotection is associated with its
antiapoptotic effect. The present study was undertaken to test the
hypothesis that MT suppresses DOX-induced apoptosis through inhibition
of mitochondrial cytochrome c release and caspase-3 activation. Primary cultures of cardiomyocytes isolated from the hearts
of transgenic neonatal mice and nontransgenic controls were treated
with DOX at a clinically relevant concentration (1.0 µM) for varying
time periods. Apoptosis was detected in nontransgenic cardiomyocyte
cultures by terminal deoxynucleotidyl transferase-mediated dUTP
nick-end labeling and Annexin V-fluorescein
isothiocyanate binding. This apoptotic effect was significantly
suppressed in the MT-overexpressing transgenic cardiomyocytes.
Western blot analysis revealed that DOX caused mitochondrial cytochrome
c release. Furthermore, caspase-3 activation was
observed. The activation of this apoptotic pathway by DOX was
dramatically inhibited in the MT-overexpressing cardiomyocytes. To
elucidate the role of reactive oxygen species (ROS) in the activation
of the cytochrome c-mediated caspase-3 activation
pathway, the intracellular levels of ROS and their localization were
detected by fluorescent confocal microscopy. Mitochondrial ROS
concentrations were dramatically elevated by DOX in nontransgenic
cardiomyocytes. This elevation was completely inhibited almost in the
MT-overexpressing cardiomyocytes. Thus, these results demonstrate that
MT suppresses DOX-induced apoptosis in cardiomyocytes through, at least
in part, inhibition of the cytochrome c-mediated
apoptotic pathway.
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