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Hypertrophic defect unmasked by calcineurin expression in asymptomatic tropomodulin overexpressing transgenic mice
- Source :
- Cardiovascular Research. 46:90-101
- Publication Year :
- 2000
- Publisher :
- Oxford University Press (OUP), 2000.
-
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.
- Subjects :
- Cardiomyopathy, Dilated
Sarcomeres
Genetically modified mouse
medicine.medical_specialty
Physiology
Transgene
Immunoblotting
Cardiomyopathy
Gene Expression
Mice, Transgenic
Breeding
Muscle hypertrophy
Mice
Myofibrils
Physiology (medical)
Internal medicine
medicine
Animals
Microscopy, Confocal
biology
Calcineurin
Myocardium
Microfilament Proteins
Hypertrophic cardiomyopathy
Dilated cardiomyopathy
Cardiomyopathy, Hypertrophic
medicine.disease
Precipitin Tests
Phenotype
Endocrinology
Animals, Newborn
biology.protein
Electrophoresis, Polyacrylamide Gel
Carrier Proteins
Cardiology and Cardiovascular Medicine
Tropomodulin
Signal Transduction
Subjects
Details
- ISSN :
- 00086363
- Volume :
- 46
- Database :
- OpenAIRE
- Journal :
- Cardiovascular Research
- Accession number :
- edsair.doi.dedup.....b84ea22e8c75f8c5d4f11520f723a83d