Document Detail


The transcription factor GATA-6 regulates pathological cardiac hypertrophy.
MedLine Citation:
PMID:  20705924     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
RATIONALE: The transcriptional code that programs maladaptive cardiac hypertrophy involves the zinc finger-containing DNA binding factor GATA-4. The highly related transcription factor GATA-6 is also expressed in the adult heart, although its role in controlling the hypertrophic program is unknown.
OBJECTIVE: To determine the role of GATA-6 in cardiac hypertrophy and homeostasis.
METHODS AND RESULTS: Here, we performed a cardiomyocyte-specific conditional gene targeting approach for Gata6, as well as a transgenic approach to overexpress GATA-6 in the mouse heart. Deletion of Gata6-loxP with Nkx2.5-cre produced late embryonic lethality with heart defects, whereas deletion with β-myosin heavy chain-cre (βMHC-cre) produced viable adults with >95% loss of GATA-6 protein in the heart. These latter mice were subjected to pressure overload-induced hypertrophy for 2 and 6 weeks, which showed a significant reduction in cardiac hypertrophy similar to that observed Gata4 heart-specific deleted mice. Gata6-deleted mice subjected to pressure overload also developed heart failure, whereas control mice maintained proper cardiac function. Gata6-deleted mice also developed less cardiac hypertrophy following 2 weeks of angiotensin II/phenylephrine infusion. Controlled GATA-6 overexpression in the heart induced hypertrophy with aging and predisposed to greater hypertrophy with pressure overload stimulation. Combinatorial deletion of Gata4 and Gata6 from the adult heart resulted in dilated cardiomyopathy and lethality by 16 weeks of age. Mechanistically, deletion of Gata6 from the heart resulted in fundamental changes in the levels of key regulatory genes and myocyte differentiation-specific genes.
CONCLUSIONS: These results indicate that GATA-6 is both necessary and sufficient for regulating the cardiac hypertrophic response and differentiated gene expression, both alone and in coordination with GATA-4.
Authors:
Jop H van Berlo; John W Elrod; Maarten M G van den Hoogenhof; Allen J York; Bruce J Aronow; Stephen A Duncan; Jeffery D Molkentin
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-08-12
Journal Detail:
Title:  Circulation research     Volume:  107     ISSN:  1524-4571     ISO Abbreviation:  Circ. Res.     Publication Date:  2010 Oct 
Date Detail:
Created Date:  2010-10-15     Completed Date:  2010-11-16     Revised Date:  2014-09-22    
Medline Journal Info:
Nlm Unique ID:  0047103     Medline TA:  Circ Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1032-40     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Blood Pressure / physiology
Cardiomegaly* / genetics,  pathology,  physiopathology
Cardiomyopathy, Dilated / genetics,  pathology,  physiopathology
Cell Differentiation / genetics
GATA4 Transcription Factor / metabolism
GATA6 Transcription Factor / genetics*,  metabolism
Gene Deletion
Heart Failure / genetics,  pathology,  physiopathology
Homeostasis / genetics
Mice
Mice, Transgenic
Transcription, Genetic / physiology
Grant Support
ID/Acronym/Agency:
P01 HL069779/HL/NHLBI NIH HHS; P01 HL069779-06A10003/HL/NHLBI NIH HHS; R01 HL062927/HL/NHLBI NIH HHS; R01 HL062927-12/HL/NHLBI NIH HHS; R37 HL060562/HL/NHLBI NIH HHS; R37 HL060562-14/HL/NHLBI NIH HHS; //Howard Hughes Medical Institute
Chemical
Reg. No./Substance:
0/GATA4 Transcription Factor; 0/GATA6 Transcription Factor; 0/Gata4 protein, mouse; 0/Gata6 protein, mouse
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