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J Biol Chem, Vol. 275, Issue 18, 13690-13698, May 5, 2000
From the Departments of Cardiomyopathy induced by doxorubicin (DOX) has
long been a major impediment of clinical applications of this effective
anticancer agent. Previous studies have shown that cardiac-specific
metallothionein (MT)-overexpressing transgenic mice are highly
resistant to DOX-induced cardiotoxicity. To investigate cellular and
molecular mechanisms by which MT participates in this cytoprotection,
transgenic mice containing high levels of cardiac MT and non-transgenic
controls were treated intraperitoneally with DOX at a single dose of 15 mg/kg and sacrificed on the 4th day after treatment. Myocardial apoptosis was detected by a terminal
deoxynucleotidyltransferase-mediated dUTP nick end labeling assay and
confirmed by electron microscopy of immunogold staining of apoptotic
nuclei. Dual staining of cardiac
Suppression by Metallothionein of Doxorubicin-induced
Cardiomyocyte Apoptosis through Inhibition of p38 Mitogen-activated
Protein Kinases*
§¶
,,,, and**
Medicine and
§ Pharmacology and Toxicology, University of Louisville,
¶ Jewish Hospital Heart and Lung Institute, and ** Veterans Affairs
Medical Center, Louisville, Kentucky 40292
-sarcomeric actin using an
immunohistochemical method further identified apoptotic myocytes.
Apoptosis was significantly inhibited in the transgenic myocardium. The
anti-apoptotic effect of MT was further revealed in primary cultures of
neonatal mouse cardiomyocytes. Furthermore, DOX activated p38
mitogen-activated protein kinase (MAPK), which was critically involved
in the apoptotic process, as demonstrated by inhibition of DOX-induced
apoptosis by a p38-specific inhibitor, SB203580. Both DOX-induced p38
MAPK activation and apoptosis were dramatically inhibited in the
transgenic cardiomyocytes. The results thus demonstrate that DOX
induces apoptosis in cardiomyocytes both in vivo and
in vitro and MT suppresses this effect through at least in
part inhibition of p38 MAPK activation.
*
This work was supported in part by National Institutes of
Health Grants CA68125 and HL59225, Established Investigator Award 9640091N from the American Heart Association National Center (to Y. J. K.), a research grant from the Department of Veterans
Affairs (to J. B. K.), and research grants from the Jewish
Hospital Foundation, Louisville, KY (to Y. J. K. and J. B. K.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
University Scholar of the University of Louisville. To whom
correspondence should be addressed: Dept. of Medicine, University of
Louisville School of Medicine, 511 S. Floyd St., MDR 530, Louisville, KY 40202. Tel.: 502-852-8677; Fax: 502-852-6904; E-mail:
yjkang01@athena.louisville.edu.
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