Genetic or pharmacologic enhancement of GATA-4 prevents cardiomyocyte apoptosis and doxorubicin-induced cardiotoxicity, indicating it is an essential antiapoptotic survival factor.
GATA-4 acts as a crucial antiapoptotic survival factor in the adult heart, and its enhancement protects against doxorubicin-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 et al. (Tue,) conducted a other in Doxorubicin-induced cardiotoxicity. Genetic or pharmacologic enhancement of GATA-4 was evaluated on Cardiomyocyte apoptosis and drug-induced cardiotoxicity. Genetic or pharmacologic enhancement of GATA-4 prevents cardiomyocyte apoptosis and doxorubicin-induced cardiotoxicity, indicating it is an essential antiapoptotic survival factor.