Document Detail

TEAD-1 overexpression in the mouse heart promotes an age-dependent heart dysfunction.
MedLine Citation:
PMID:  20194497     Owner:  NLM     Status:  MEDLINE    
TEA domain transcription factor-1 (TEAD-1) is essential for proper heart development and is implicated in cardiac specific gene expression and the hypertrophic response of primary cardiomyocytes to hormonal and mechanical stimuli, and its activity increases in the pressure-overloaded hypertrophied rat heart. To investigate whether TEAD-1 is an in vivo modulator of cardiac specific gene expression and hypertrophy, we developed transgenic mice expressing hemagglutinin-tagged TEAD-1 under the control of the muscle creatine kinase promoter. We show that a sustained increase in TEAD-1 protein leads to an age-dependent dysfunction. Magnetic resonance imaging revealed decreases in cardiac output, stroke volume, ejection fraction, and fractional shortening. Isolated TEAD-1 hearts revealed decreased left ventricular power output that correlated with increased betaMyHC protein. Histological analysis showed altered alignment of cardiomyocytes, septal wall thickening, and fibrosis, although electrocardiography displayed a left axis shift of mean electrical axis. Transcripts representing most members of the fetal heart gene program remained elevated from fetal to adult life. Western blot analyses revealed decreases in p-phospholamban, SERCA2a, p-CX43, p-GSK-3alpha/beta, nuclear beta-catenin, GATA4, NFATc3/c4, and increased NCX1, nuclear DYKR1A, and Pur alpha/beta protein. TEAD-1 mice did not display cardiac hypertrophy. TEAD-1 mice do not tolerate stress as they die over a 4-day period after surgical induction of pressure overload. These data provide the first in vivo evidence that increased TEAD-1 can induce characteristics of cardiac remodeling associated with cardiomyopathy and heart failure.
Richard W Tsika; Lixin Ma; Izhak Kehat; Christine Schramm; Gretchen Simmer; Brandon Morgan; Deborah M Fine; Laurin M Hanft; Kerry S McDonald; Jeffery D Molkentin; Maike Krenz; Steve Yang; Juan Ji
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2010-03-01
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  285     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2010 Apr 
Date Detail:
Created Date:  2010-04-26     Completed Date:  2010-05-27     Revised Date:  2013-05-30    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  13721-35     Citation Subset:  IM    
Department of Biochemistry, School of Medicine, University of Missouri, Columbia, Missouri 65211, USA.
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MeSH Terms
Cardiomegaly / genetics,  metabolism*,  pathology
DNA-Binding Proteins / biosynthesis*,  genetics
Fibrosis / metabolism,  pathology
Heart Failure / genetics,  metabolism*,  pathology
Mice, Transgenic
Muscle Proteins / biosynthesis*,  genetics
Myocardium / metabolism*,  pathology
Myocytes, Cardiac / metabolism*,  pathology
Organ Specificity / genetics
Promoter Regions, Genetic / genetics
Stress, Physiological / genetics
Stroke Volume / genetics
Transcription Factors / biosynthesis*,  genetics
Grant Support
Reg. No./Substance:
0/DNA-Binding Proteins; 0/Muscle Proteins; 0/Tead1 protein, mouse; 0/Transcription Factors

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