Essential role of GATA-4 in cell survival and drug-induced cardiotoxicity.
In recent years, significant progress has been made in understanding cardiomyocyte differentiation. However, little is known about the regulation of myocyte survival despite the fact that myocyte apoptosis is a leading cause of heart failure. Here we report that transcription factor GATA-4 is a survival factor for differentiated, postnatal cardiomyocytes and an upstream activator of the antiapoptotic gene Bcl-X. An early event in the cardiotoxic effect of the antitumor drug doxorubicin is GATA-4 depletion, which in turn causes cardiomyocyte apoptosis. Mouse heterozygotes for a null Gata4 allele have enhanced susceptibility to doxorubicin cardiotoxicity. Genetic or pharmacologic enhancement of GATA-4 prevents cardiomyocyte apoptosis and drug-induced cardiotoxicity. The results indicate that GATA-4 is an antiapoptotic factor required for the adaptive stress response of the adult heart. Modulation of survival/apoptosis genes by tissue-specific transcription factors may be a general paradigm that can be exploited effectively for cell-specific regulation of apoptosis in disease states.
Aries
Anne
A
Laboratory of Cardiac Growth and Differentiation, Institut de Recherches Cliniques de Montréal, Montréal, QC, Canada H2W 1R7.
Paradis
Pierre
P
Lefebvre
Chantal
C
Schwartz
Robert J
RJ
Nemer
Mona
M
D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D017209:Apoptosis / Q000502:physiology; D002470:Cell Survival / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004317:Doxorubicin / Q000633:toxicity*; D050991:GATA4 Transcription Factor; D032383:Myocytes, Cardiac / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D051020:bcl-X Protein
D000903:Antibiotics, Antineoplastic; D004268:DNA-Binding Proteins; D050991:GATA4 Transcription Factor; D019253:Proto-Oncogene Proteins c-bcl-2; D014157:Transcription Factors; D051020:bcl-X Protein; D004317:Doxorubicin