title: Transcription enhancer factor-1-related factor-transgenic mice develop cardiac conduction defects associated with altered connexin phosphorylation.
abstract: BACKGROUND
  Conduction system defects and slowed ventricular conduction are common in patients with systolic dysfunction and contribute to arrhythmias and sudden death. In animal models of heart failure, cardiac alpha1-adrenergic signaling is constitutively activated. Here, we report the effects of constitutive activation of alpha1-adrenergic signaling on connexin phosphorylation and cardiac conduction.
  
  
  RESULTS
  Transgenic mice were generated with cardiac-specific overexpression of the transcription factor RTEF-1 (transcription enhancer factor-1-related factor), which mediates alpha1-adrenergic signaling in cardiac myocytes. Surface and intracardiac ECGs revealed prolongation of the PR, QRS, and AH intervals and the appearance of progressive atrial arrhythmias in RTEF-1 mice. Optical mapping using voltage-sensitive dye revealed slower conduction velocities across the atrial and ventricular myocardium. Intercellular dye transfer between RTEF-1 transgenic cardiac myocytes confirmed impaired conduction at the cellular level. Conduction defects were correlated with dephosphorylation of connexin40 and connexin43 and upregulation of protein phosphatase 1beta (PP1beta). Overexpression of PP1beta in HeLa cells dephosphorylated cardiac connexin. Confocal microscopy revealed increased levels of dephosphorylated connexin43 at the cardiac gap junctions in RTEF-1 mice, suggesting that defective conduction is a result of impaired gap-junction conductance rather than assembly.
  
  
  CONCLUSIONS
  Constitutive activation of alpha1-adrenergic signaling through the RTEF-1 transcription factor results in chronic elevation of PP1beta expression and connexin dephosphorylation. This mechanism may underlie some defects in cardiac conduction.
authors.affiliation: Cardiovascular Institute, University of Pittsburgh, Pittsburgh, Pa 15213, USA.
authors.forename: Hsiao-Huei
authors.initials: HH
authors.lastname: Chen
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Baty
authors.forename: Tomoji
authors.initials: T
authors.lastname: Maeda
authors.forename: Steven
authors.initials: S
authors.lastname: Brooks
authors.forename: Linda C
authors.initials: LC
authors.lastname: Baker
authors.forename: Takahisa
authors.initials: T
authors.lastname: Ueyama
authors.forename: Erdal
authors.initials: E
authors.lastname: Gursoy
authors.forename: Samir
authors.initials: S
authors.lastname: Saba
authors.forename: Guy
authors.initials: G
authors.lastname: Salama
authors.forename: Barry
authors.initials: B
authors.lastname: London
authors.forename: Alexandre F R
authors.initials: AF
authors.lastname: Stewart
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics / Q000503:physiopathology*; D002478:Cells, Cultured / Q000502:physiology; D018031:Connexin 43 / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D004562:Electrocardiography; D017629:Gap Junctions / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology*; D006367:HeLa Cells / Q000378:metabolism; D006325:Heart Atria / Q000503:physiopathology; D006329:Heart Conduction System / Q000503:physiopathology*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009124:Muscle Proteins / Q000235:genetics / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000502:physiology*; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation; D054645:Protein Phosphatase 1; D011499:Protein Processing, Post-Translational; D018340:Receptors, Adrenergic, alpha-1 / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D000091262:TEA Domain Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
chemical_list: D018031:Connexin 43; D004268:DNA-Binding Proteins; D009124:Muscle Proteins; D018340:Receptors, Adrenergic, alpha-1; D011993:Recombinant Fusion Proteins; D000091262:TEA Domain Transcription Factors; C486309:TEAD4 protein, human; D014157:Transcription Factors; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1