title: Calcium/calmodulin-dependent protein kinase II couples Wnt signaling with histone deacetylase 4 and mediates dishevelled-induced cardiomyopathy.
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.
authors.affiliation: From the Department of Cardiology, Angiology, and Pulmology (M.Z., M.H., J.H.R., M.M.K., E.B., J.F., H.A.K., S.E.H.) and Research Unit Cardiac Epigenetics, Department of Cardiology (M.M.K., J.B.), University of Heidelberg, Heidelberg, Germany; Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China (M.Z.); DZHK (German Center for Cardiovascular Research) (M.H., J.H.R., M.M.K., H.A.K., S.E.H., M.M.K., J.B.), Partner Site Heidelberg/Mannheim, Heidelberg, Germany; and Center for Cardiac and Circulatory Diseases, Bruchsal, Germany (S.E.H.).
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.affiliation: From the Department of Cardiology, Angiology, and Pulmology (M.Z., M.H., J.H.R., M.M.K., E.B., J.F., H.A.K., S.E.H.) and Research Unit Cardiac Epigenetics, Department of Cardiology (M.M.K., J.B.), University of Heidelberg, Heidelberg, Germany; Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China (M.Z.); DZHK (German Center for Cardiovascular Research) (M.H., J.H.R., M.M.K., H.A.K., S.E.H., M.M.K., J.B.), Partner Site Heidelberg/Mannheim, Heidelberg, Germany; and Center for Cardiac and Circulatory Diseases, Bruchsal, Germany (S.E.H.).
authors.forename: Marco
authors.initials: M
authors.lastname: Hagenmueller
authors.affiliation: From the Department of Cardiology, Angiology, and Pulmology (M.Z., M.H., J.H.R., M.M.K., E.B., J.F., H.A.K., S.E.H.) and Research Unit Cardiac Epigenetics, Department of Cardiology (M.M.K., J.B.), University of Heidelberg, Heidelberg, Germany; Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China (M.Z.); DZHK (German Center for Cardiovascular Research) (M.H., J.H.R., M.M.K., H.A.K., S.E.H., M.M.K., J.B.), Partner Site Heidelberg/Mannheim, Heidelberg, Germany; and Center for Cardiac and Circulatory Diseases, Bruchsal, Germany (S.E.H.).
authors.forename: Johannes H
authors.initials: JH
authors.lastname: Riffel
authors.affiliation: From the Department of Cardiology, Angiology, and Pulmology (M.Z., M.H., J.H.R., M.M.K., E.B., J.F., H.A.K., S.E.H.) and Research Unit Cardiac Epigenetics, Department of Cardiology (M.M.K., J.B.), University of Heidelberg, Heidelberg, Germany; Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China (M.Z.); DZHK (German Center for Cardiovascular Research) (M.H., J.H.R., M.M.K., H.A.K., S.E.H., M.M.K., J.B.), Partner Site Heidelberg/Mannheim, Heidelberg, Germany; and Center for Cardiac and Circulatory Diseases, Bruchsal, Germany (S.E.H.).
authors.forename: Michael M
authors.initials: MM
authors.lastname: Kreusser
authors.affiliation: From the Department of Cardiology, Angiology, and Pulmology (M.Z., M.H., J.H.R., M.M.K., E.B., J.F., H.A.K., S.E.H.) and Research Unit Cardiac Epigenetics, Department of Cardiology (M.M.K., J.B.), University of Heidelberg, Heidelberg, Germany; Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China (M.Z.); DZHK (German Center for Cardiovascular Research) (M.H., J.H.R., M.M.K., H.A.K., S.E.H., M.M.K., J.B.), Partner Site Heidelberg/Mannheim, Heidelberg, Germany; and Center for Cardiac and Circulatory Diseases, Bruchsal, Germany (S.E.H.).
authors.forename: Elmar
authors.initials: E
authors.lastname: Bernhold
authors.affiliation: From the Department of Cardiology, Angiology, and Pulmology (M.Z., M.H., J.H.R., M.M.K., E.B., J.F., H.A.K., S.E.H.) and Research Unit Cardiac Epigenetics, Department of Cardiology (M.M.K., J.B.), University of Heidelberg, Heidelberg, Germany; Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China (M.Z.); DZHK (German Center for Cardiovascular Research) (M.H., J.H.R., M.M.K., H.A.K., S.E.H., M.M.K., J.B.), Partner Site Heidelberg/Mannheim, Heidelberg, Germany; and Center for Cardiac and Circulatory Diseases, Bruchsal, Germany (S.E.H.).
authors.forename: Jingjing
authors.initials: J
authors.lastname: Fan
authors.affiliation: From the Department of Cardiology, Angiology, and Pulmology (M.Z., M.H., J.H.R., M.M.K., E.B., J.F., H.A.K., S.E.H.) and Research Unit Cardiac Epigenetics, Department of Cardiology (M.M.K., J.B.), University of Heidelberg, Heidelberg, Germany; Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China (M.Z.); DZHK (German Center for Cardiovascular Research) (M.H., J.H.R., M.M.K., H.A.K., S.E.H., M.M.K., J.B.), Partner Site Heidelberg/Mannheim, Heidelberg, Germany; and Center for Cardiac and Circulatory Diseases, Bruchsal, Germany (S.E.H.).
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.affiliation: From the Department of Cardiology, Angiology, and Pulmology (M.Z., M.H., J.H.R., M.M.K., E.B., J.F., H.A.K., S.E.H.) and Research Unit Cardiac Epigenetics, Department of Cardiology (M.M.K., J.B.), University of Heidelberg, Heidelberg, Germany; Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China (M.Z.); DZHK (German Center for Cardiovascular Research) (M.H., J.H.R., M.M.K., H.A.K., S.E.H., M.M.K., J.B.), Partner Site Heidelberg/Mannheim, Heidelberg, Germany; and Center for Cardiac and Circulatory Diseases, Bruchsal, Germany (S.E.H.).
authors.forename: Johannes
authors.initials: J
authors.lastname: Backs
authors.affiliation: From the Department of Cardiology, Angiology, and Pulmology (M.Z., M.H., J.H.R., M.M.K., E.B., J.F., H.A.K., S.E.H.) and Research Unit Cardiac Epigenetics, Department of Cardiology (M.M.K., J.B.), University of Heidelberg, Heidelberg, Germany; Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China (M.Z.); DZHK (German Center for Cardiovascular Research) (M.H., J.H.R., M.M.K., H.A.K., S.E.H., M.M.K., J.B.), Partner Site Heidelberg/Mannheim, Heidelberg, Germany; and Center for Cardiac and Circulatory Diseases, Bruchsal, Germany (S.E.H.). stefanhardt@outlook.com.
authors.forename: Stefan E
authors.initials: SE
authors.lastname: Hardt
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000818:Animals; D017209:Apoptosis; D001596:Benzylamines / Q000494:pharmacology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000502:physiology*; D000072261:Dishevelled Proteins; D005355:Fibrosis; D006333:Heart Failure / Q000201:enzymology* / Q000503:physiopathology / Q000517:prevention & control; D006655:Histone Deacetylases / Q000502:physiology*; D017379:Hypertrophy, Left Ventricular / Q000000981:diagnostic imaging / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D020935:MAP Kinase Signaling System; D064326:MEF2 Transcription Factors / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000473:pathology; D010641:Phenotype; D010750:Phosphoproteins / Q000502:physiology*; D011493:Protein Kinase C / Q000502:physiology; D013449:Sulfonamides / Q000494:pharmacology; D014463:Ultrasonography; D018487:Ventricular Dysfunction, Left / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D020257:Ventricular Remodeling; D051153:Wnt Proteins / Q000502:physiology*; D060449:Wnt Signaling Pathway / Q000502:physiology*; D051176:beta Catenin / Q000502:physiology; D000096926:Benzenesulfonamides
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001596:Benzylamines; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D000072261:Dishevelled Proteins; D006655:Histone Deacetylases; D064326:MEF2 Transcription Factors; D010750:Phosphoproteins; D011493:Protein Kinase C; D013449:Sulfonamides; D051153:Wnt Proteins; D051176:beta Catenin; C000606579:Dvl1 protein, mouse; C578036:Mef2a protein, mouse; C578039:Mef2b protein, mouse; C072105:KN 93; D000096926:Benzenesulfonamides; C498618:Hdac5 protein, mouse
keywords: Wnt signaling pathway; calcium-calmodulin-dependent protein kinase type 2; cardiomyopathies; dishevelled proteins; histone deacetylase 4