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Cardiovascular Research 2000 46(1):90-101; doi:10.1016/S0008-6363(99)00422-8
© 2000 by European Society of Cardiology
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Copyright © 2000, European Society of Cardiology

Hypertrophic defect unmasked by calcineurin expression in asymptomatic tropomodulin overexpressing transgenic mice

Mark A. Sussmana,*, Sara Welcha, Angela Walkera, Raisa Klevitskya, Timothy E. Hewetta, Sandra A. Wittb, Thomas R. Kimballb, Robert Pricec, Hae W. Lima and Jeffery D. Molkentina

aThe Children's Hospital and Research Foundation, Division of Molecular Cardiovascular Biology, Room 3033, 3333 Burnet Avenue, Cincinnati, OH 45229, USA
bThe Children's Hospital and Research Foundation, Division of Cardiology, 3333 Burnet Avenue, Cincinnati, OH 45229, USA
cUniversity of South Carolina, Department of Cell Biology and Anatomy, Columbia, SC, USA

* Corresponding author. Tel.: +1-513-636-7145; fax: +1-513-636-8966 sussman{at}heart.chmcc.org

Objective: Dilation and hypertrophy often occur concurrently in cardiomyopathy, yet the interaction between these two functionally distinct conditions remains unknown. Methods: Combinatorial effects of hypertrophy and dilation were investigated by cross-breeding of two cardiomyopathic transgenic mouse lines which develop either hypertrophy (calcineurin-mediated) or dilation (tropomodulin-mediated). Results: Altering the intensity of signals driving hypertrophy and dilation in cross-bred litters resulted in novel disease phenotypes different from either parental line. Augmenting the calcineurin-dependent hypertrophic stimulus in tropomodulin overexpressing transgenics elevated heart:body weight ratios, increased ventricular wall thickness, and significantly accelerated mortality. These effects were evident in calcineurin cross-breeding to tropomodulin backgrounds of transgene homozygosity (severe dilation) or heterozygosity (mild dilation to asymptomatic). Molecular analyses indicated that tropomodulin and calcineurin signaling events in the first week after birth were critical for determination of disease outcome, substantiated by demonstration that temporary neonatal inhibition of tropomodulin expression prevents dilation. Conclusions: This study shows that postnatal timing of altered signaling in cardiomyopathic transgenic mouse models is a pivotal part of determining outcome. In addition, intensifying hypertrophic stimulation exacerbates dilated cardiomyopathy, supporting the concept of shared molecular signaling between hypertrophy and dilation.

KEYWORDS Cardiomyopathy; Contractile function; Heart failure; Hypertrophy; Signal transduction


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