Reversal of cardiac hypertrophy in transgenic disease models by calcineurin inhibition.
Heart disease remains one of the leading causes of morbidity and mortality in the industrialized nations of the world. Intense investigation has centered around identifying and manipulating intracellular signaling pathways that direct hypertrophic and myopathic responses in an attempt to intervene in the progression or reverse certain forms of heart disease. We show here that cyclosporin A-mediated inhibition of the calcium-regulated phosphatase, calcineurin (PP2B), reverses cardiac hypertrophy and myopathic dilation in two transgenic mouse models of cardiomyopathy. Reversal was demonstrated by gravimetric analysis, echocardiography, histological analysis, and molecular analysis of hypertrophy-associated gene expression. In contrast, a third mouse model of hypertrophic cardiomyopathy due to activated NFAT3 cardiac-specific expression was not affected by cyclosporin A. These results suggest that calcineurin may function in the long-term maintenance of cardiac hypertrophy or myopathic disease states.
Lim
H W
HW
Department of Pediatrics, Division of Molecular Cardiovascular Biology, Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH 45229-3039, USA.
De Windt
L J
LJ
Mante
J
J
Kimball
T R
TR
Witt
S A
SA
Sussman
M A
MA
Molkentin
J D
JD
D000818:Animals; D019703:Calcineurin / Q000235:genetics; D065095:Calcineurin Inhibitors; D006332:Cardiomegaly / Q000503:physiopathology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D010641:Phenotype; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D051348:Tropomodulin
D065095:Calcineurin Inhibitors; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D008840:Microfilament Proteins; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; C495831:Tmod1 protein, mouse; D014157:Transcription Factors; D051348:Tropomodulin; D016572:Cyclosporine; D019703:Calcineurin