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 ␤MyHC 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-3␣/␤, nuclear ␤-catenin, GATA4, NFATc3/c4, and increased NCX1, nuclear DYKR1A, and Pur␣/␤ 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.

Negative Regulation of the Thyrotropin β Gene by Thyroid Hormone

“…TEF family transcription factors are the major target of 1 adrenaline signaling (Chen et al, 2004), which is known to mimic the cardiac phenotype seen in heart failure (Yoshida, 2008). Consistently, overexpression of TEF-1 in vivo exhibits a phenotype similar to that of chronic heart failure (Tsika et al, 2010). Our preliminary data suggests that T3/TR inhibits TEF-dependent transactivation of the MHC gene.…”

Regulation of Myocardial Cell Growth and Death by the Hippo Pathway

“…74 On the other hand, TEAD1 overexpression in the postnatal mouse heart upregulates the fetal-type gene program and induces age-dependent dysfunction. 75 These findings suggest that Yap-TEAD interaction is necessary for embryonic heart growth fully elucidated. However, it is known that the Hippo pathway plays a crucial role in regulating cardiac development.…”

Tead1 is required for maintaining adult cardiomyocyte function, and its loss results in lethal dilated cardiomyopathy

“…While, a decrease in Serca2a and Pln phosphorylation was seen in these mice with heart failure, it is unclear if these were secondary to heart failure. Interestingly, both Tead1-overexpressing transgenic (42) and Tead1-deleted mice from our study displayed decreased contractile function. Consistent with the Tsika et al study that Tead1 overexpression upregulated β-MHC, Tead1-deletion, in our study, led to a significant decrease in β-MHC (data not shown), suggesting that Tead1 is a potent regulator of β-MHC.…”