title: Cardiac CaM Kinase II genes δ and γ contribute to adverse remodeling but redundantly inhibit calcineurin-induced myocardial hypertrophy.
abstract: BACKGROUND
  Ca(2+)-dependent signaling through CaM Kinase II (CaMKII) and calcineurin was suggested to contribute to adverse cardiac remodeling. However, the relative importance of CaMKII versus calcineurin for adverse cardiac remodeling remained unclear.
  
  
  RESULTS
  We generated double-knockout mice (DKO) lacking the 2 cardiac CaMKII genes δ and γ specifically in cardiomyocytes. We show that both CaMKII isoforms contribute redundantly to phosphorylation not only of phospholamban, ryanodine receptor 2, and histone deacetylase 4, but also calcineurin. Under baseline conditions, DKO mice are viable and display neither abnormal Ca(2+) handling nor functional and structural changes. On pathological pressure overload and β-adrenergic stimulation, DKO mice are protected against cardiac dysfunction and interstitial fibrosis. But surprisingly and paradoxically, DKO mice develop cardiac hypertrophy driven by excessive activation of endogenous calcineurin, which is associated with a lack of phosphorylation at the auto-inhibitory calcineurin A site Ser411. Likewise, calcineurin inhibition prevents cardiac hypertrophy in DKO. On exercise performance, DKO mice show an exaggeration of cardiac hypertrophy with increased expression of the calcineurin target gene RCAN1-4 but no signs of adverse cardiac remodeling.
  
  
  CONCLUSIONS
  We established a mouse model in which CaMKII's activity is specifically and completely abolished. By the use of this model we show that CaMKII induces maladaptive cardiac remodeling while it inhibits calcineurin-dependent hypertrophy. These data suggest inhibition of CaMKII but not calcineurin as a promising approach to attenuate the progression of heart failure.
authors.affiliation: From the Research Unit Cardiac Epigenetics, Department of Cardiology, University of Heidelberg, and DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany (M.M.K., L.H.L., S.K., M.-O.H., U.O., J.B.); Department of Cardiology, Saarland University, Homburg, Germany (M.K., J.-C.R., C.M.); Department of Internal Medicine II, University of Regensburg, Germany (K.N., L.S.M.); British Heart Foundation Centre of Research Excellence, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, United Kingdom (M.D.S.); Department of Internal Medicine, University of Southwestern Texas Medical Center, Dallas (J.A.H.); Institute of Pharmacology, University of Duisburg-Essen, Germany (D.D.); Department of Molecular Pathology, German Cancer Research Center, Heidelberg, Germany (H.-J.G.); Department of Cardiology, University of Heidelberg, and DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany (H.A.K.); and the Department of Molecular Biology, University of Southwestern Texas Medical Center, Dallas (E.N.O.).
authors.forename: Michael M
authors.initials: MM
authors.lastname: Kreusser
authors.affiliation: From the Research Unit Cardiac Epigenetics, Department of Cardiology, University of Heidelberg, and DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany (M.M.K., L.H.L., S.K., M.-O.H., U.O., J.B.); Department of Cardiology, Saarland University, Homburg, Germany (M.K., J.-C.R., C.M.); Department of Internal Medicine II, University of Regensburg, Germany (K.N., L.S.M.); British Heart Foundation Centre of Research Excellence, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, United Kingdom (M.D.S.); Department of Internal Medicine, University of Southwestern Texas Medical Center, Dallas (J.A.H.); Institute of Pharmacology, University of Duisburg-Essen, Germany (D.D.); Department of Molecular Pathology, German Cancer Research Center, Heidelberg, Germany (H.-J.G.); Department of Cardiology, University of Heidelberg, and DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany (H.A.K.); and the Department of Molecular Biology, University of Southwestern Texas Medical Center, Dallas (E.N.O.).
authors.forename: Lorenz H
authors.initials: LH
authors.lastname: Lehmann
authors.affiliation: From the Research Unit Cardiac Epigenetics, Department of Cardiology, University of Heidelberg, and DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany (M.M.K., L.H.L., S.K., M.-O.H., U.O., J.B.); Department of Cardiology, Saarland University, Homburg, Germany (M.K., J.-C.R., C.M.); Department of Internal Medicine II, University of Regensburg, Germany (K.N., L.S.M.); British Heart Foundation Centre of Research Excellence, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, United Kingdom (M.D.S.); Department of Internal Medicine, University of Southwestern Texas Medical Center, Dallas (J.A.H.); Institute of Pharmacology, University of Duisburg-Essen, Germany (D.D.); Department of Molecular Pathology, German Cancer Research Center, Heidelberg, Germany (H.-J.G.); Department of Cardiology, University of Heidelberg, and DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany (H.A.K.); and the Department of Molecular Biology, University of Southwestern Texas Medical Center, Dallas (E.N.O.).
authors.forename: Stanislav
authors.initials: S
authors.lastname: Keranov
authors.affiliation: From the Research Unit Cardiac Epigenetics, Department of Cardiology, University of Heidelberg, and DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany (M.M.K., L.H.L., S.K., M.-O.H., U.O., J.B.); Department of Cardiology, Saarland University, Homburg, Germany (M.K., J.-C.R., C.M.); Department of Internal Medicine II, University of Regensburg, Germany (K.N., L.S.M.); British Heart Foundation Centre of Research Excellence, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, United Kingdom (M.D.S.); Department of Internal Medicine, University of Southwestern Texas Medical Center, Dallas (J.A.H.); Institute of Pharmacology, University of Duisburg-Essen, Germany (D.D.); Department of Molecular Pathology, German Cancer Research Center, Heidelberg, Germany (H.-J.G.); Department of Cardiology, University of Heidelberg, and DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany (H.A.K.); and the Department of Molecular Biology, University of Southwestern Texas Medical Center, Dallas (E.N.O.).
authors.forename: Marc-Oscar
authors.initials: MO
authors.lastname: Hoting
authors.affiliation: From the Research Unit Cardiac Epigenetics, Department of Cardiology, University of Heidelberg, and DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany (M.M.K., L.H.L., S.K., M.-O.H., U.O., J.B.); Department of Cardiology, Saarland University, Homburg, Germany (M.K., J.-C.R., C.M.); Department of Internal Medicine II, University of Regensburg, Germany (K.N., L.S.M.); British Heart Foundation Centre of Research Excellence, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, United Kingdom (M.D.S.); Department of Internal Medicine, University of Southwestern Texas Medical Center, Dallas (J.A.H.); Institute of Pharmacology, University of Duisburg-Essen, Germany (D.D.); Department of Molecular Pathology, German Cancer Research Center, Heidelberg, Germany (H.-J.G.); Department of Cardiology, University of Heidelberg, and DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany (H.A.K.); and the Department of Molecular Biology, University of Southwestern Texas Medical Center, Dallas (E.N.O.).
authors.forename: Ulrike
authors.initials: U
authors.lastname: Oehl
authors.affiliation: From the Research Unit Cardiac Epigenetics, Department of Cardiology, University of Heidelberg, and DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany (M.M.K., L.H.L., S.K., M.-O.H., U.O., J.B.); Department of Cardiology, Saarland University, Homburg, Germany (M.K., J.-C.R., C.M.); Department of Internal Medicine II, University of Regensburg, Germany (K.N., L.S.M.); British Heart Foundation Centre of Research Excellence, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, United Kingdom (M.D.S.); Department of Internal Medicine, University of Southwestern Texas Medical Center, Dallas (J.A.H.); Institute of Pharmacology, University of Duisburg-Essen, Germany (D.D.); Department of Molecular Pathology, German Cancer Research Center, Heidelberg, Germany (H.-J.G.); Department of Cardiology, University of Heidelberg, and DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany (H.A.K.); and the Department of Molecular Biology, University of Southwestern Texas Medical Center, Dallas (E.N.O.).
authors.forename: Michael
authors.initials: M
authors.lastname: Kohlhaas
authors.affiliation: From the Research Unit Cardiac Epigenetics, Department of Cardiology, University of Heidelberg, and DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany (M.M.K., L.H.L., S.K., M.-O.H., U.O., J.B.); Department of Cardiology, Saarland University, Homburg, Germany (M.K., J.-C.R., C.M.); Department of Internal Medicine II, University of Regensburg, Germany (K.N., L.S.M.); British Heart Foundation Centre of Research Excellence, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, United Kingdom (M.D.S.); Department of Internal Medicine, University of Southwestern Texas Medical Center, Dallas (J.A.H.); Institute of Pharmacology, University of Duisburg-Essen, Germany (D.D.); Department of Molecular Pathology, German Cancer Research Center, Heidelberg, Germany (H.-J.G.); Department of Cardiology, University of Heidelberg, and DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany (H.A.K.); and the Department of Molecular Biology, University of Southwestern Texas Medical Center, Dallas (E.N.O.).
authors.forename: Jan-Christian
authors.initials: JC
authors.lastname: Reil
authors.affiliation: From the Research Unit Cardiac Epigenetics, Department of Cardiology, University of Heidelberg, and DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany (M.M.K., L.H.L., S.K., M.-O.H., U.O., J.B.); Department of Cardiology, Saarland University, Homburg, Germany (M.K., J.-C.R., C.M.); Department of Internal Medicine II, University of Regensburg, Germany (K.N., L.S.M.); British Heart Foundation Centre of Research Excellence, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, United Kingdom (M.D.S.); Department of Internal Medicine, University of Southwestern Texas Medical Center, Dallas (J.A.H.); Institute of Pharmacology, University of Duisburg-Essen, Germany (D.D.); Department of Molecular Pathology, German Cancer Research Center, Heidelberg, Germany (H.-J.G.); Department of Cardiology, University of Heidelberg, and DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany (H.A.K.); and the Department of Molecular Biology, University of Southwestern Texas Medical Center, Dallas (E.N.O.).
authors.forename: Kay
authors.initials: K
authors.lastname: Neumann
authors.affiliation: From the Research Unit Cardiac Epigenetics, Department of Cardiology, University of Heidelberg, and DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany (M.M.K., L.H.L., S.K., M.-O.H., U.O., J.B.); Department of Cardiology, Saarland University, Homburg, Germany (M.K., J.-C.R., C.M.); Department of Internal Medicine II, University of Regensburg, Germany (K.N., L.S.M.); British Heart Foundation Centre of Research Excellence, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, United Kingdom (M.D.S.); Department of Internal Medicine, University of Southwestern Texas Medical Center, Dallas (J.A.H.); Institute of Pharmacology, University of Duisburg-Essen, Germany (D.D.); Department of Molecular Pathology, German Cancer Research Center, Heidelberg, Germany (H.-J.G.); Department of Cardiology, University of Heidelberg, and DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany (H.A.K.); and the Department of Molecular Biology, University of Southwestern Texas Medical Center, Dallas (E.N.O.).
authors.forename: Michael D
authors.initials: MD
authors.lastname: Schneider
authors.affiliation: From the Research Unit Cardiac Epigenetics, Department of Cardiology, University of Heidelberg, and DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany (M.M.K., L.H.L., S.K., M.-O.H., U.O., J.B.); Department of Cardiology, Saarland University, Homburg, Germany (M.K., J.-C.R., C.M.); Department of Internal Medicine II, University of Regensburg, Germany (K.N., L.S.M.); British Heart Foundation Centre of Research Excellence, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, United Kingdom (M.D.S.); Department of Internal Medicine, University of Southwestern Texas Medical Center, Dallas (J.A.H.); Institute of Pharmacology, University of Duisburg-Essen, Germany (D.D.); Department of Molecular Pathology, German Cancer Research Center, Heidelberg, Germany (H.-J.G.); Department of Cardiology, University of Heidelberg, and DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany (H.A.K.); and the Department of Molecular Biology, University of Southwestern Texas Medical Center, Dallas (E.N.O.).
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Hill
authors.affiliation: From the Research Unit Cardiac Epigenetics, Department of Cardiology, University of Heidelberg, and DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany (M.M.K., L.H.L., S.K., M.-O.H., U.O., J.B.); Department of Cardiology, Saarland University, Homburg, Germany (M.K., J.-C.R., C.M.); Department of Internal Medicine II, University of Regensburg, Germany (K.N., L.S.M.); British Heart Foundation Centre of Research Excellence, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, United Kingdom (M.D.S.); Department of Internal Medicine, University of Southwestern Texas Medical Center, Dallas (J.A.H.); Institute of Pharmacology, University of Duisburg-Essen, Germany (D.D.); Department of Molecular Pathology, German Cancer Research Center, Heidelberg, Germany (H.-J.G.); Department of Cardiology, University of Heidelberg, and DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany (H.A.K.); and the Department of Molecular Biology, University of Southwestern Texas Medical Center, Dallas (E.N.O.).
authors.forename: Dobromir
authors.initials: D
authors.lastname: Dobrev
authors.affiliation: From the Research Unit Cardiac Epigenetics, Department of Cardiology, University of Heidelberg, and DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany (M.M.K., L.H.L., S.K., M.-O.H., U.O., J.B.); Department of Cardiology, Saarland University, Homburg, Germany (M.K., J.-C.R., C.M.); Department of Internal Medicine II, University of Regensburg, Germany (K.N., L.S.M.); British Heart Foundation Centre of Research Excellence, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, United Kingdom (M.D.S.); Department of Internal Medicine, University of Southwestern Texas Medical Center, Dallas (J.A.H.); Institute of Pharmacology, University of Duisburg-Essen, Germany (D.D.); Department of Molecular Pathology, German Cancer Research Center, Heidelberg, Germany (H.-J.G.); Department of Cardiology, University of Heidelberg, and DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany (H.A.K.); and the Department of Molecular Biology, University of Southwestern Texas Medical Center, Dallas (E.N.O.).
authors.forename: Christoph
authors.initials: C
authors.lastname: Maack
authors.affiliation: From the Research Unit Cardiac Epigenetics, Department of Cardiology, University of Heidelberg, and DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany (M.M.K., L.H.L., S.K., M.-O.H., U.O., J.B.); Department of Cardiology, Saarland University, Homburg, Germany (M.K., J.-C.R., C.M.); Department of Internal Medicine II, University of Regensburg, Germany (K.N., L.S.M.); British Heart Foundation Centre of Research Excellence, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, United Kingdom (M.D.S.); Department of Internal Medicine, University of Southwestern Texas Medical Center, Dallas (J.A.H.); Institute of Pharmacology, University of Duisburg-Essen, Germany (D.D.); Department of Molecular Pathology, German Cancer Research Center, Heidelberg, Germany (H.-J.G.); Department of Cardiology, University of Heidelberg, and DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany (H.A.K.); and the Department of Molecular Biology, University of Southwestern Texas Medical Center, Dallas (E.N.O.).
authors.forename: Lars S
authors.initials: LS
authors.lastname: Maier
authors.affiliation: From the Research Unit Cardiac Epigenetics, Department of Cardiology, University of Heidelberg, and DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany (M.M.K., L.H.L., S.K., M.-O.H., U.O., J.B.); Department of Cardiology, Saarland University, Homburg, Germany (M.K., J.-C.R., C.M.); Department of Internal Medicine II, University of Regensburg, Germany (K.N., L.S.M.); British Heart Foundation Centre of Research Excellence, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, United Kingdom (M.D.S.); Department of Internal Medicine, University of Southwestern Texas Medical Center, Dallas (J.A.H.); Institute of Pharmacology, University of Duisburg-Essen, Germany (D.D.); Department of Molecular Pathology, German Cancer Research Center, Heidelberg, Germany (H.-J.G.); Department of Cardiology, University of Heidelberg, and DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany (H.A.K.); and the Department of Molecular Biology, University of Southwestern Texas Medical Center, Dallas (E.N.O.).
authors.forename: Hermann-Josef
authors.initials: HJ
authors.lastname: Gröne
authors.affiliation: From the Research Unit Cardiac Epigenetics, Department of Cardiology, University of Heidelberg, and DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany (M.M.K., L.H.L., S.K., M.-O.H., U.O., J.B.); Department of Cardiology, Saarland University, Homburg, Germany (M.K., J.-C.R., C.M.); Department of Internal Medicine II, University of Regensburg, Germany (K.N., L.S.M.); British Heart Foundation Centre of Research Excellence, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, United Kingdom (M.D.S.); Department of Internal Medicine, University of Southwestern Texas Medical Center, Dallas (J.A.H.); Institute of Pharmacology, University of Duisburg-Essen, Germany (D.D.); Department of Molecular Pathology, German Cancer Research Center, Heidelberg, Germany (H.-J.G.); Department of Cardiology, University of Heidelberg, and DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany (H.A.K.); and the Department of Molecular Biology, University of Southwestern Texas Medical Center, Dallas (E.N.O.).
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.affiliation: From the Research Unit Cardiac Epigenetics, Department of Cardiology, University of Heidelberg, and DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany (M.M.K., L.H.L., S.K., M.-O.H., U.O., J.B.); Department of Cardiology, Saarland University, Homburg, Germany (M.K., J.-C.R., C.M.); Department of Internal Medicine II, University of Regensburg, Germany (K.N., L.S.M.); British Heart Foundation Centre of Research Excellence, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, United Kingdom (M.D.S.); Department of Internal Medicine, University of Southwestern Texas Medical Center, Dallas (J.A.H.); Institute of Pharmacology, University of Duisburg-Essen, Germany (D.D.); Department of Molecular Pathology, German Cancer Research Center, Heidelberg, Germany (H.-J.G.); Department of Cardiology, University of Heidelberg, and DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany (H.A.K.); and the Department of Molecular Biology, University of Southwestern Texas Medical Center, Dallas (E.N.O.).
authors.forename: Eric N
authors.initials: EN
authors.lastname: Olson
authors.affiliation: From the Research Unit Cardiac Epigenetics, Department of Cardiology, University of Heidelberg, and DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany (M.M.K., L.H.L., S.K., M.-O.H., U.O., J.B.); Department of Cardiology, Saarland University, Homburg, Germany (M.K., J.-C.R., C.M.); Department of Internal Medicine II, University of Regensburg, Germany (K.N., L.S.M.); British Heart Foundation Centre of Research Excellence, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, United Kingdom (M.D.S.); Department of Internal Medicine, University of Southwestern Texas Medical Center, Dallas (J.A.H.); Institute of Pharmacology, University of Duisburg-Essen, Germany (D.D.); Department of Molecular Pathology, German Cancer Research Center, Heidelberg, Germany (H.-J.G.); Department of Cardiology, University of Heidelberg, and DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany (H.A.K.); and the Department of Molecular Biology, University of Southwestern Texas Medical Center, Dallas (E.N.O.). johannes.backs@med.uni-heidelberg.de.
authors.forename: Johannes
authors.initials: J
authors.lastname: Backs
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000378:metabolism*; D020013:Calcium Signaling / Q000235:genetics / Q000502:physiology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D006332:Cardiomegaly / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D006333:Heart Failure / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009206:Myocardium / Q000201:enzymology*; D050778:NFATC Transcription Factors / Q000378:metabolism; D010805:Physical Conditioning, Animal / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D020257:Ventricular Remodeling / Q000235:genetics* / Q000502:physiology
chemical_list: D050778:NFATC Transcription Factors; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D019703:Calcineurin
keywords: CaMKII; calcineurin; cardiac hypertrophy; heart failure; signal transduction