Abstract
In response to numerous pathologic stimuli, the myocardium undergoes a hypertrophic response characterized by increased myocardial cell size and activation of fetal cardiac genes. We show that cardiac hypertrophy is induced by the calcium-dependent phosphatase calcineurin, which dephosphorylates the transcription factor NF-AT3, enabling it to translocate to the nucleus. NF-AT3 interacts with the cardiac zinc finger transcription factor GATA4, resulting in synergistic activation of cardiac transcription. Transgenic mice that express activated forms of calcineurin or NF-AT3 in the heart develop cardiac hypertrophy and heart failure that mimic human heart disease. Pharmacologic inhibition of calcineurin activity blocks hypertrophy in vivo and in vitro. These results define a novel hypertrophic signaling pathway and suggest pharmacologic approaches to prevent cardiac hypertrophy and heart failure.
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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Angiotensin II / pharmacology
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Animals
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Animals, Newborn
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Atrial Natriuretic Factor / genetics
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Calcineurin / genetics
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Calcineurin / physiology*
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Cardiomegaly / enzymology
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Cardiomegaly / genetics*
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Cardiomegaly / prevention & control
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Cell Nucleus / metabolism
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DNA-Binding Proteins / metabolism
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GATA4 Transcription Factor
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Immunosuppressive Agents / pharmacology
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Mice
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Mice, Transgenic
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Myocardium / metabolism
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Myocardium / pathology*
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NFATC Transcription Factors
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Natriuretic Peptide, Brain
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Nuclear Proteins*
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Phenylephrine / pharmacology
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Promoter Regions, Genetic / genetics
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Rats
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Recombinant Fusion Proteins
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Signal Transduction / physiology*
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Transcription Factors / metabolism
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Transcription, Genetic
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Transcriptional Activation / physiology*
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Zinc Fingers
Substances
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DNA-Binding Proteins
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GATA4 Transcription Factor
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Immunosuppressive Agents
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NFATC Transcription Factors
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NFATC4 protein, human
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Nuclear Proteins
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Recombinant Fusion Proteins
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Transcription Factors
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Angiotensin II
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Natriuretic Peptide, Brain
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Phenylephrine
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Atrial Natriuretic Factor
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Calcineurin