Abstract
Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and calcineurin (CaN) are positive regulators of cardiac hypertrophy, but the nature of cross-talk between CaMKII and CaN signaling pathways in hypertrophic cardiomyocytes remains unclear. Here we documented that CaMKIIdelta3 activation enhances transcription of the CaN gene through activation of the CaN-Abeta subunit (CnAbeta) promoter in rat cultured cardiomyocytes. Co-immunoprecipitation assays showed that MEF2 forms a complex with GATA4 following transfection of an active CaMKIIdelta3 (T278D) mutant in neonatal cardiomyocytes. Inversely, transfection of a dominant negative CaMKIIdelta3 mutant failed to promote a MEF2-GATA4 complex. Consistent with these observations, immunocytochemistry indicated nuclear co-localization of MEF2 with GATA4 after hypertrophic agonist stimulation or CaMKIIdelta3 (T278D) transfection. These data demonstrate that CaMKII can enhance CnAbeta promoter activity by enhancing MEF2-GATA4 synergy, suggesting a novel mechanism for CaMKII-mediated hypertrophic signaling, which contributes to induction and development of the hypertrophic response through CaN activation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Active Transport, Cell Nucleus
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Animals
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Base Sequence
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Calcineurin / genetics*
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Calcium Signaling
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Calcium-Calmodulin-Dependent Protein Kinase Type 2 / antagonists & inhibitors
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Calcium-Calmodulin-Dependent Protein Kinase Type 2 / genetics
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Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism*
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Cardiomegaly / etiology
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Cardiomegaly / genetics
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Cardiomegaly / metabolism
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Cell Size
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Cells, Cultured
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DNA Primers / genetics
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Endothelin-1 / metabolism*
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Endothelin-1 / pharmacology
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GATA4 Transcription Factor / metabolism
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In Vitro Techniques
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Models, Cardiovascular
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Mutagenesis, Site-Directed
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Myocytes, Cardiac / drug effects
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Myocytes, Cardiac / metabolism*
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Myogenic Regulatory Factors / metabolism
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Promoter Regions, Genetic
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Rats
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Signal Transduction
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Transfection
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Up-Regulation / drug effects
Substances
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DNA Primers
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Endothelin-1
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GATA4 Transcription Factor
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Gata4 protein, rat
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Myogenic Regulatory Factors
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RNA, Messenger
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Recombinant Fusion Proteins
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Calcium-Calmodulin-Dependent Protein Kinase Type 2
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Calcineurin