title: Relevance of calmodulin/CaMKII activation for arrhythmogenesis in the AV block dog.
abstract: BACKGROUND
  The calcium-dependent signaling molecules calcineurin and calcium/calmodulin-dependent protein kinase II (CaMKII) both have been linked to decompensated hypertrophy and arrhythmias. CaMKII is also believed to be involved in acute modulation of ion channels.
  
  
  OBJECTIVE
  The purpose of this study was to determine the role of calcineurin and CaMKII in a dog model of compensated hypertrophy and a long QT phenotype.
  
  
  METHODS
  AV block was created in dogs to induce ventricular remodeling, including enhanced susceptibility to dofetilide-induced torsades de pointes arrhythmias. Dogs were treated with cyclosporin A for 3 weeks, which reduced calcineurin activity, as determined by mRNA expression levels of regulator of calcineurin 1 exon 4, but which was unable to prevent structural, contractile, or electrical remodeling and arrhythmias. Biopsies were taken before and at 2 or 9 weeks after AV block. Western blots were performed against phosphorylated and total CaMKII, phospholamban, Akt, and histone deacetylase 4 (HDAC4).
  
  
  RESULTS
  Chronic AV block showed an increase in Akt, CaMKII and phospholamban phosphorylation levels, but HDAC4 phosphorylation remained unaltered. Dofetilide induced torsades de pointes in vivo and early afterdepolarizations in cardiomyocytes, and increased [Ca(2+)](i) and CaMKII autophosphorylation. Both W-7 and KN-93 treatment counteracted this.
  
  
  CONCLUSIONS
  The calcineurin pathway seems not to be involved in long-term cardiac remodeling of the chronic AV block dog. Although CaMKII is chronically activated, this does not translate to HDAC4 phosphorylation. However, acute CaMKII overactivation is able to initiate arrhythmias based on triggered activity.
authors: Department of Medical Physiology, Division Heart & Lungs, University Medical Center Utrecht, Utrecht, The Netherlands. v.j.a.bourgonje@umcutrecht.nl
authors: Vincent J A
authors: VJ
authors: Bourgonje
authors: Marieke
authors: M
authors: Schoenmakers
authors: Jet D M
authors: JD
authors: Beekman
authors: Roel
authors: R
authors: van der Nagel
authors: Marien J C
authors: MJ
authors: Houtman
authors: Lars F
authors: LF
authors: Miedema
authors: Gudrun
authors: G
authors: Antoons
authors: Karin
authors: K
authors: Sipido
authors: Leon J
authors: LJ
authors: de Windt
authors: Toon A B
authors: TA
authors: van Veen
authors: Marc A
authors: MA
authors: Vos
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000378:metabolism* / Q000503:physiopathology; D054537:Atrioventricular Block / Q000378:metabolism* / Q000503:physiopathology; D001596:Benzylamines / Q000494:pharmacology; D019703:Calcineurin / Q000502:physiology*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000502:physiology*; D002312:Cardiomyopathy, Hypertrophic / Q000378:metabolism* / Q000503:physiopathology; D016572:Cyclosporine / Q000494:pharmacology; D004195:Disease Models, Animal; D004285:Dogs; D007545:Isoproterenol / Q000494:pharmacology; D008133:Long QT Syndrome / Q000378:metabolism* / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000187:drug effects; D018408:Patch-Clamp Techniques; D010627:Phenethylamines / Q000494:pharmacology; D010641:Phenotype; D010766:Phosphorylation; D011897:Random Allocation; D013449:Sulfonamides / Q000494:pharmacology; D020257:Ventricular Remodeling; D000099211:Phospholamban; D000096926:Benzenesulfonamides
chemical_list: D001596:Benzylamines; D019703:Calcineurin; D002135:Calcium-Binding Proteins; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D016572:Cyclosporine; D007545:Isoproterenol; D010627:Phenethylamines; D013449:Sulfonamides; D000099211:Phospholamban; C072105:KN 93; D000096926:Benzenesulfonamides; C017967:W 7; C063533:dofetilide