Cardiac-specific deletion of Gata4 reveals its requirement for hypertrophy, compensation, and myocyte viability.
The transcription factor GATA4 is a critical regulator of cardiac gene expression where it controls embryonic development, cardiomyocyte differentiation, and stress responsiveness of the adult heart. Traditional deletion of Gata4 caused embryonic lethality associated with endoderm defects and cardiac malformations, precluding an analysis of the role of GATA4 in the adult myocardium. To address the function of GATA4 in the adult heart, Gata4-loxP-targeted mice (Gata4fl/fl) were crossed with mice containing a beta-myosin heavy chain (beta-MHC) or alpha-MHC promoter-driven Cre transgene, which produced viable mice that survived into adulthood despite a 95% and 70% loss of GATA4 protein, respectively. However, cardiac-specific deletion of Gata4 resulted in a progressive and dosage-dependent deterioration in cardiac function and dilation in adulthood. Moreover, pressure overload stimulation induced rapid decompensation and heart failure in cardiac-specific Gata4-deleted mice. More provocatively, Gata4-deleted mice were compromised in their ability to hypertrophy following pressure overload or exercise stimulation. Mechanistically, cardiac-specific deletion of Gata4 increased cardiomyocyte TUNEL at baseline in embryos and adults as they aged, as well as dramatically increased TUNEL following pressure overload stimulation. Examination of gene expression profiles in the heart revealed a number of profound alterations in known GATA4-regulated structural genes as well as genes with apoptotic implications. Thus, GATA4 is a necessary regulator of cardiac gene expression, hypertrophy, stress-compensation, and myocyte viability.
Oka
Toru
T
Department of Pediatrics, University of Cincinnati, Children's Hospital Medical Center, Ohio 45229-3039, USA.
Maillet
Marjorie
M
Watt
Alistair J
AJ
Schwartz
Robert J
RJ
Aronow
Bruce J
BJ
Duncan
Stephen A
SA
Molkentin
Jeffery D
JD
D000818:Animals; D017209:Apoptosis; D009320:Atrial Natriuretic Factor / Q000235:genetics; D006332:Cardiomegaly / Q000209:etiology*; D002470:Cell Survival; D050991:GATA4 Transcription Factor / Q000235:genetics / Q000502:physiology*; D017353:Gene Deletion; D005786:Gene Expression Regulation; D051379:Mice; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000502:physiology*; D018995:Myosin Heavy Chains / Q000235:genetics
D050991:GATA4 Transcription Factor; C484171:Gata4 protein, mouse; D009320:Atrial Natriuretic Factor; D018995:Myosin Heavy Chains