Abstract
Activation of Wnt signaling results in maladaptive cardiac remodeling and cardiomyopathy. Recently, calcium/calmodulin-dependent protein kinase II (CaMKII) was reported to be a pivotal participant in myocardial remodeling. Because CaMKII was suggested as a downstream target of noncanonical Wnt signaling, we aimed to elucidate the role of CaMKII in dishevelled-1-induced cardiomyopathy and the mechanisms underlying its function. Dishevelled-1-induced cardiomyopathy was reversed by deletion of neither CaMKIIδ nor CaMKIIγ. Therefore, dishevelled-1-transgenic mice were crossed with CaMKIIδγ double-knockout mice. These mice displayed a normal cardiac phenotype without cardiac hypertrophy, fibrosis, apoptosis, or left ventricular dysfunction. Further mechanistic analyses unveiled that CaMKIIδγ couples noncanonical Wnt signaling to histone deacetylase 4 and myosin enhancer factor 2. Therefore, our findings indicate that the axis, consisting of dishevelled-1, CaMKII, histone deacetylase 4, and myosin enhancer factor 2, is an attractive therapeutic target for prevention of cardiac remodeling and its progression to left ventricular dysfunction.
Keywords:
Wnt signaling pathway; calcium-calmodulin-dependent protein kinase type 2; cardiomyopathies; dishevelled proteins; histone deacetylase 4.
© 2014 American Heart Association, Inc.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / physiology*
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Animals
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Apoptosis
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Benzylamines / pharmacology
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Calcium-Calmodulin-Dependent Protein Kinase Type 2 / antagonists & inhibitors
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Calcium-Calmodulin-Dependent Protein Kinase Type 2 / deficiency
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Calcium-Calmodulin-Dependent Protein Kinase Type 2 / physiology*
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Dishevelled Proteins
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Fibrosis
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Heart Failure / enzymology*
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Heart Failure / physiopathology
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Heart Failure / prevention & control
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Histone Deacetylases / physiology*
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Hypertrophy, Left Ventricular / diagnostic imaging
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Hypertrophy, Left Ventricular / enzymology*
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Hypertrophy, Left Ventricular / genetics
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Hypertrophy, Left Ventricular / physiopathology
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MAP Kinase Signaling System
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MEF2 Transcription Factors / physiology
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Mice
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Mice, Knockout
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Myocardium / pathology
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Phenotype
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Phosphoproteins / physiology*
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Protein Kinase C / physiology
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Sulfonamides / pharmacology
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Ultrasonography
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Ventricular Dysfunction, Left / enzymology*
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Ventricular Dysfunction, Left / genetics
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Ventricular Dysfunction, Left / physiopathology
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Ventricular Remodeling
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Wnt Proteins / physiology*
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Wnt Signaling Pathway / physiology*
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beta Catenin / physiology
Substances
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Adaptor Proteins, Signal Transducing
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Benzylamines
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Dishevelled Proteins
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Dvl1 protein, mouse
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MEF2 Transcription Factors
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Mef2a protein, mouse
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Mef2b protein, mouse
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Phosphoproteins
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Sulfonamides
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Wnt Proteins
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beta Catenin
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KN 93
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Protein Kinase C
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Calcium-Calmodulin-Dependent Protein Kinase Type 2
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Hdac5 protein, mouse
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Histone Deacetylases