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

Mark A. Sussman, Sara Welch, Angela Walker, Raisa Klevitsky, Timothy E. Hewett, Sandra A. Witt, Thomas R. Kimball, Robert Price, Hae W. Lim, Jeffery D. Molkentin

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

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. (C) 2000 Elsevier Science B.V.

Original languageEnglish (US)
Pages (from-to)90-101
Number of pages12
JournalCardiovascular research
Volume46
Issue number1
DOIs
StatePublished - Apr 1 2000

Keywords

  • Cardiomyopathy
  • Contractile function
  • Heart failure
  • Hypertrophy
  • Signal transduction

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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    Sussman, M. A., Welch, S., Walker, A., Klevitsky, R., Hewett, T. E., Witt, S. A., Kimball, T. R., Price, R., Lim, H. W., & Molkentin, J. D. (2000). Hypertrophic defect unmasked by calcineurin expression in asymptomatic tropomodulin overexpressing transgenic mice. Cardiovascular research, 46(1), 90-101. https://doi.org/10.1016/S0008-6363(99)00422-8