Abstract
Hypertrophic cardiomyopathy (HCM) is an inherited form of heart disease that affects 1 in 500 individuals. Here it is shown that calcineurin, a calcium-regulated phosphatase, plays a critical role in the pathogenesis of HCM. Administration of the calcineurin inhibitors cyclosporin and FK506 prevented disease in mice that were genetically predisposed to develop HCM as a result of aberrant expression of tropomodulin, myosin light chain-2, or fetal beta-tropomyosin in the heart. Cyclosporin had a similar effect in a rat model of pressure-overload hypertrophy. These results suggest that calcineurin inhibitors merit investigation as potential therapeutics for certain forms of human heart disease.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Calcineurin / metabolism
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Calcineurin Inhibitors*
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Calcium / metabolism
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Cardiac Myosins*
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Cardiomegaly / metabolism
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Cardiomegaly / pathology
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Cardiomegaly / prevention & control*
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Cardiomyopathy, Dilated / pathology
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Cardiomyopathy, Dilated / prevention & control*
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Cardiomyopathy, Hypertrophic / genetics
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Cardiomyopathy, Hypertrophic / metabolism
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Cardiomyopathy, Hypertrophic / pathology
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Cardiomyopathy, Hypertrophic / prevention & control*
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Carrier Proteins / genetics
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Cyclosporine / pharmacology*
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Female
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Mice
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Mice, Transgenic
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Microfilament Proteins*
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Models, Cardiovascular
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Myocardium / metabolism*
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Myocardium / pathology
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Myosin Light Chains / genetics
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Myosin Light Chains / metabolism
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Rats
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Signal Transduction
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Tacrolimus / pharmacology*
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Tropomodulin
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Tropomyosin / genetics
Substances
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Calcineurin Inhibitors
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Carrier Proteins
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Microfilament Proteins
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Myosin Light Chains
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Tmod1 protein, mouse
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Tmod1 protein, rat
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Tropomodulin
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Tropomyosin
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myosin light chain 2
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Cyclosporine
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Calcineurin
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Cardiac Myosins
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Calcium
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Tacrolimus