title: Essential role of GATA-4 in cell survival and drug-induced cardiotoxicity.
abstract: 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.
authors.affiliation: Laboratory of Cardiac Growth and Differentiation, Institut de Recherches Cliniques de Montréal, Montréal, QC, Canada H2W 1R7.
authors.forename: Anne
authors.initials: A
authors.lastname: Aries
authors.forename: Pierre
authors.initials: P
authors.lastname: Paradis
authors.forename: Chantal
authors.initials: C
authors.lastname: Lefebvre
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Schwartz
authors.forename: Mona
authors.initials: M
authors.lastname: Nemer
mesh_terms: 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
chemical_list: 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