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Molecular Pharmacology

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Research ArticleArticle

Anthracycline-Induced Suppression of GATA-4 Transcription Factor: Implication in the Regulation of Cardiac Myocyte Apoptosis

Yuri Kim, Ai-Guo Ma, Kazumi Kitta, Sarah N. Fitch, Takayuki Ikeda, Yoshiharu Ihara, Amy R. Simon, Todd Evans and Yuichiro J. Suzuki
Molecular Pharmacology February 2003, 63 (2) 368-377; DOI: https://doi.org/10.1124/mol.63.2.368
Yuri Kim
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Ai-Guo Ma
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Kazumi Kitta
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Sarah N. Fitch
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Takayuki Ikeda
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Yoshiharu Ihara
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Amy R. Simon
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Todd Evans
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Yuichiro J. Suzuki
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Abstract

Anthracyclines are effective cancer chemotherapeutic agents but can induce serious cardiotoxicity. Understanding the mechanism of cardiac damage by these agents will help in development of better therapeutic strategies against cancer. The GATA-4 transcription factor is an important regulator of cardiac muscle cells. The present study demonstrates that anthracyclines can down-regulate GATA-4 activity. Treatment of HL-1 cardiac muscle cells or isolated adult rat ventricular myocytes with anthracyclines such as daunorubicin and doxorubicin decreased the level of GATA-4 DNA-binding activity. The mechanism of decreased GATA-4 activity acts at the level of the GATA-4 gene, because anthracyclines caused significantly decreased levels of GATA-4 protein and mRNA. The rate of decline in GATA-4 transcript levels in the presence of actinomycin D was unaltered by anthracyclines, indicating that these agents may affect directly GATA-4 gene transcription. To determine whether decreased GATA-4 levels are functionally related to cardiac muscle cell death that can be induced by anthracyclines, the ability of ectopic GATA factors to rescue anthracycline-induced apoptosis was tested. Adenovirus-mediated expression of either GATA-4 or GATA-6 was sufficient to attenuate the incidence of apoptosis. Furthermore, suppression of GATA-4 DNA-binding activity by a dominant negative mutant of GATA-4 induced the apoptosis. These results suggest that the mechanism of anthracycline-induced cardiotoxicity may involve the down-regulation of GATA-4 and the induction of apoptosis.

Footnotes

  • This work was supported by grants from the American Heart Association New England Affiliate (to Y.J.S.) and National Institutes of Health HL64282 (to T.E.). This material is based upon work supported by the U.S. Department of Agriculture under cooperative agreement 58-1950-9-001.

  • Abbreviations:
    DNR
    daunorubicin
    DOX
    doxorubicin
    ROS
    reactive oxygen species
    EMSA
    electrophoretic mobility shift assay
    RT
    reverse transcription
    PCR
    polymerase chain reaction
    PARP
    poly(ADP-ribose) polymerase
    TNFα
    tumor necrosis factor-α
    • Received July 10, 2002.
    • Accepted October 23, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 63 (2)
Molecular Pharmacology
Vol. 63, Issue 2
1 Feb 2003
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Research ArticleArticle

Anthracycline-Induced Suppression of GATA-4 Transcription Factor: Implication in the Regulation of Cardiac Myocyte Apoptosis

Yuri Kim, Ai-Guo Ma, Kazumi Kitta, Sarah N. Fitch, Takayuki Ikeda, Yoshiharu Ihara, Amy R. Simon, Todd Evans and Yuichiro J. Suzuki
Molecular Pharmacology February 1, 2003, 63 (2) 368-377; DOI: https://doi.org/10.1124/mol.63.2.368

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Research ArticleArticle

Anthracycline-Induced Suppression of GATA-4 Transcription Factor: Implication in the Regulation of Cardiac Myocyte Apoptosis

Yuri Kim, Ai-Guo Ma, Kazumi Kitta, Sarah N. Fitch, Takayuki Ikeda, Yoshiharu Ihara, Amy R. Simon, Todd Evans and Yuichiro J. Suzuki
Molecular Pharmacology February 1, 2003, 63 (2) 368-377; DOI: https://doi.org/10.1124/mol.63.2.368
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