Abstract
The heart responds to stress signals by hypertrophic growth, which is accompanied by activation of the MEF2 transcription factor and reprogramming of cardiac gene expression. We show here that class II histone deacetylases (HDACs), which repress MEF2 activity, are substrates for a stress-responsive kinase specific for conserved serines that regulate MEF2-HDAC interactions. Signal-resistant HDAC mutants lacking these phosphorylation sites are refractory to hypertrophic signaling and inhibit cardiomyocyte hypertrophy. Conversely, mutant mice lacking the class II HDAC, HDAC9, are sensitized to hypertrophic signals and exhibit stress-dependent cardiomegaly. Thus, class II HDACs act as signal-responsive suppressors of the transcriptional program governing 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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Aging / genetics
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Aging / metabolism
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Aging / pathology
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Animals
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Calcineurin / genetics
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Calcineurin / metabolism
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Calcium-Calmodulin-Dependent Protein Kinase Type 1
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Calcium-Calmodulin-Dependent Protein Kinases / genetics
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism
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Cardiomegaly / enzymology*
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Cardiomegaly / genetics
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Cardiomegaly / physiopathology
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Carrier Proteins / genetics
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Carrier Proteins / metabolism
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Enzyme Inhibitors / pharmacology
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Gene Expression Regulation, Developmental / physiology*
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Heart / embryology
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Histone Deacetylase 2
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Histone Deacetylases / deficiency*
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Histone Deacetylases / genetics
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Histone Deacetylases / metabolism
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Hypertension / complications
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Hypertension / pathology
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Hypertension / physiopathology
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MEF2 Transcription Factors
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Male
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Mice
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Mice, Knockout
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Mutation / genetics
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Myocardium / enzymology
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Myocardium / pathology
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Myogenic Regulatory Factors
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Phosphorylation
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Phosphotransferases / genetics
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Phosphotransferases / metabolism
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Repressor Proteins*
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Signal Transduction / genetics*
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Stress, Physiological / enzymology*
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Stress, Physiological / genetics
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Stress, Physiological / physiopathology
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Transcriptional Activation / physiology*
Substances
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Carrier Proteins
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DNA-Binding Proteins
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Enzyme Inhibitors
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MEF2 Transcription Factors
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Myogenic Regulatory Factors
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Repressor Proteins
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Transcription Factors
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Phosphotransferases
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CAMK1 protein, human
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Calcium-Calmodulin-Dependent Protein Kinase Type 1
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Calcium-Calmodulin-Dependent Protein Kinases
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Camk1 protein, mouse
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Pnck protein, mouse
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Calcineurin
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HDAC9 protein, human
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Hdac2 protein, mouse
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Hdac5 protein, mouse
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Hdac9 protein, mouse
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Histone Deacetylase 2
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Histone Deacetylases