Prevention of cardiac hypertrophy in mice by calcineurin inhibition.
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.
Sussman
M A
MA
Division of Molecular Cardiovascular Biology, Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.
Lim
H W
HW
Gude
N
N
Taigen
T
T
Olson
E N
EN
Robbins
J
J
Colbert
M C
MC
Gualberto
A
A
Wieczorek
D F
DF
Molkentin
J D
JD
D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D065095:Calcineurin Inhibitors; D002118:Calcium / Q000378:metabolism; D024722:Cardiac Myosins; D006332:Cardiomegaly / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002311:Cardiomyopathy, Dilated / Q000473:pathology / Q000517:prevention & control*; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002352:Carrier Proteins / Q000235:genetics; D016572:Cyclosporine / Q000494:pharmacology*; D005260:Female; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins; D008955:Models, Cardiovascular; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D018994:Myosin Light Chains / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D016559:Tacrolimus / Q000494:pharmacology*; D051348:Tropomodulin; D014335:Tropomyosin / Q000235:genetics
D065095:Calcineurin Inhibitors; D002352:Carrier Proteins; D008840:Microfilament Proteins; D018994:Myosin Light Chains; C495831:Tmod1 protein, mouse; C495832:Tmod1 protein, rat; D051348:Tropomodulin; D014335:Tropomyosin; C107184:myosin light chain 2; D016572:Cyclosporine; D019703:Calcineurin; D024722:Cardiac Myosins; D002118:Calcium; D016559:Tacrolimus