Essential role of GATA-4 in cell survival and drug-induced cardiotoxicity

被引:236
作者
Aries, A
Paradis, P
Lefebvre, C
Schwartz, RJ
Nemer, M
机构
[1] Clin Res Inst Montreal, Lab Cardiac Growth & Differentiat, Montreal, PQ H2W 1R7, Canada
[2] Univ Montreal, Dept Pharmacol, Montreal, PQ H3C 3J7, Canada
[3] Baylor Coll Med, Dept Cell Biol, Houston, TX 77030 USA
关键词
transcription; apoptosis; Bcl-X; doxorubicin; alpha l-adrenergic receptors;
D O I
10.1073/pnas.0401833101
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 cardionnyocyte apoptosis. Mouse heterozygotes for a null Gata4 allele have enhanced susceptibility to doxorubicin cardiotoxicity. Genetic or pharmacologic enhancement of GATA-4 prevents cardionnyocyte 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.
引用
收藏
页码:6975 / 6980
页数:6
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