Targeted inhibition of calcineurin prevents agonist-induced cardiomyocyte hypertrophy.
Cardiac hypertrophy is a major predictor of future morbidity and mortality. Recent investigation has centered around identifying the molecular signaling pathways that regulate cardiac myocyte reactivity with the goal of modulating pathologic hypertrophic programs. One potential regulator of cardiomyocyte hypertrophy is the calcium-sensitive phosphatase calcineurin. We show here that calcineurin enzymatic activity, mRNA, and protein levels are increased in cultured neonatal rat cardiomyocytes by hypertrophic agonists such as angiotensin II, phenylephrine, and 1% fetal bovine serum. This induction of calcineurin activity was associated with an increase in calcineurin Abeta (CnAbeta) mRNA and protein, but not in CnAalpha or CnAgamma. Agonist-dependent increases in calcineurin enzymatic activity were specifically inhibited with an adenovirus expressing a noncompetitive peptide inhibitor of calcineurin known as cain [Lai, M. M., Burnett, P. E., Wolosker, H., Blackshaw, S. & Snyder, S. H. (1998) J. Biol. Chem. 273, 18325-18331]. Targeted inhibition of calcineurin with cain or an adenovirus expressing only the calcineurin inhibitory domain of AKAP79 attenuated cardiomyocyte hypertrophy and atrial natriuretic factor expression in response to angiotensin II, phenylephrine, and 1% fetal bovine serum. These data demonstrate that calcineurin is an important regulator of cardiomyocyte hypertrophy in response to certain agonists and suggest that cyclosporin A and FK506 function to attenuate cardiac hypertrophy by specifically inhibiting calcineurin.
Taigen
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Division of Molecular Cardiovascular Biology, Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA.
De Windt
L J
LJ
Lim
H W
HW
Molkentin
J D
JD
D000256:Adenoviridae / Q000235:genetics; D000804:Angiotensin II / Q000633:toxicity; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D009320:Atrial Natriuretic Factor / Q000096:biosynthesis / Q000235:genetics; D019703:Calcineurin / Q000096:biosynthesis / Q000235:genetics; D065095:Calcineurin Inhibitors; D006332:Cardiomegaly / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D002352:Carrier Proteins / Q000235:genetics / Q000627:therapeutic use*; D002417:Cattle; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D005312:Fetal Blood; D005786:Gene Expression Regulation / Q000187:drug effects; D005796:Genes; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics / Q000627:therapeutic use*; D006984:Hypertrophy; D009206:Myocardium / Q000473:pathology; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D010656:Phenylephrine / Q000633:toxicity; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism; D014162:Transfection
D051017:Apoptosis Regulatory Proteins; C113573:Cabin1 protein, rat; D065095:Calcineurin Inhibitors; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D014157:Transcription Factors; D000804:Angiotensin II; D010656:Phenylephrine; D009320:Atrial Natriuretic Factor; D019703:Calcineurin