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Hypertrophic defect unmasked by calcineurin expression in asymptomatic tropomodulin overexpressing transgenic mice
M A Sussman1, S Welch, A Walker
1The Children's Hospital and Research Foundation, Division of Molecular Cardiovascular Biology, Room 3033, 3333 Burnet Avenue, Cincinnati, OH 45229, USA. sussman@heart.chmcc.org
Insights
Interactions between cardiac hypertrophy and dilation were studied in mice. Intensifying hypertrophy signals worsened dilated cardiomyopathy, suggesting shared molecular pathways and highlighting the importance of postnatal signaling timing.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Genetics of Heart Disease
Background:
- Cardiomyopathy often involves both cardiac dilation and hypertrophy.
- The interplay between these two distinct conditions is not well understood.
Purpose of the Study:
- To investigate the combined effects of hypertrophy and dilation in a mouse model.
- To explore the molecular mechanisms underlying their interaction.
Main Methods:
- Cross-breeding of two transgenic mouse lines: one with calcineurin-mediated hypertrophy, the other with tropomodulin-mediated dilation.
- Analysis of resulting phenotypes and molecular signaling pathways.
Main Results:
- Cross-bred mice exhibited novel phenotypes distinct from parental lines.
- Increased hypertrophic stimulus in dilated hearts led to higher mortality and worsened cardiac remodeling.
- Postnatal signaling via tropomodulin and calcineurin pathways critically determined disease outcomes.
Conclusions:
- Postnatal signaling timing is crucial in determining cardiomyopathy outcomes in transgenic models.
- Intensified hypertrophic stimulation exacerbates dilated cardiomyopathy, indicating shared signaling pathways.
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.