Hypertrophic defect unmasked by calcineurin expression in asymptomatic tropomodulin overexpressing transgenic mice.
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.
Sussman
M A
MA
The Children's Hospital and Research Foundation, Division of Molecular Cardiovascular Biology, Room 3033, 3333 Burnet Avenue, Cincinnati, OH 45229, USA. sussman@heart.chmcc.org
Welch
S
S
Walker
A
A
Klevitsky
R
R
Hewett
T E
TE
Witt
S A
SA
Kimball
T R
TR
Price
R
R
Lim
H W
HW
Molkentin
J D
JD
D000818:Animals; D000831:Animals, Newborn; D001947:Breeding; D019703:Calcineurin / Q000235:genetics* / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D015870:Gene Expression; D015151:Immunoblotting; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins; D018613:Microscopy, Confocal; D009206:Myocardium / Q000473:pathology / Q000648:ultrastructure; D009210:Myofibrils / Q000473:pathology / Q000648:ultrastructure; D010641:Phenotype; D011233:Precipitin Tests; D012518:Sarcomeres / Q000648:ultrastructure; D015398:Signal Transduction / Q000187:drug effects; D051348:Tropomodulin
D002352:Carrier Proteins; D008840:Microfilament Proteins; C495831:Tmod1 protein, mouse; D051348:Tropomodulin; D019703:Calcineurin