title: TEAD-1 overexpression in the mouse heart promotes an age-dependent heart dysfunction.
abstract: 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.
authors.affiliation: Department of Biochemistry, School of Medicine, University of Missouri, Columbia, Missouri 65211, USA. tsikar@missouri.edu
authors.forename: Richard W
authors.initials: RW
authors.lastname: Tsika
authors.forename: Lixin
authors.initials: L
authors.lastname: Ma
authors.forename: Izhak
authors.initials: I
authors.lastname: Kehat
authors.forename: Christine
authors.initials: C
authors.lastname: Schramm
authors.forename: Gretchen
authors.initials: G
authors.lastname: Simmer
authors.forename: Brandon
authors.initials: B
authors.lastname: Morgan
authors.forename: Deborah M
authors.initials: DM
authors.lastname: Fine
authors.forename: Laurin M
authors.initials: LM
authors.lastname: Hanft
authors.forename: Kerry S
authors.initials: KS
authors.lastname: McDonald
authors.forename: Jeffery D
authors.initials: JD
authors.lastname: Molkentin
authors.forename: Maike
authors.initials: M
authors.lastname: Krenz
authors.forename: Steve
authors.initials: S
authors.lastname: Yang
authors.forename: Juan
authors.initials: J
authors.lastname: Ji
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009124:Muscle Proteins / Q000096:biosynthesis* / Q000235:genetics; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D009928:Organ Specificity / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D013312:Stress, Physiological / Q000235:genetics; D013318:Stroke Volume / Q000235:genetics; D000091262:TEA Domain Transcription Factors; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D009124:Muscle Proteins; D000091262:TEA Domain Transcription Factors; C083215:Tead1 protein, mouse; D014157:Transcription Factors