title: A peptide mimetic of the connexin43 carboxyl terminus reduces gap junction remodeling and induced arrhythmia following ventricular injury.
abstract: BACKGROUND
  Remodeling of connexin (Cx)43 gap junctions (GJs) is linked to ventricular arrhythmia.
  
  
  OBJECTIVE
  A peptide mimetic of the carboxyl terminal (CT) of Cx43, incorporating a postsynaptic density-95/disks-large/ZO-1 (PDZ)-binding domain, reduces Cx43/ZO-1 interaction and GJ size remodeling in vitro. Here, we determined: (1) whether the Cx43-CT mimetic αCT1 altered GJ remodeling following left ventricular (LV) injury in vivo; (2) whether αCT1 affected arrhythmic propensity; and (3) the mechanism of αCT1 effects on arrhythmogenicity and GJ remodeling.
  
  
  RESULTS
  A cryoinjury model generating a reproducible wound and injury border zone (IBZ) in the LV was used. Adherent methylcellulose patches formulated to locally release αCT1 (< 48 hours) were placed on cryoinjuries. Relative to controls, Cx43/ZO-1 colocalization in the IBZ was reduced by αCT1 by 24 hours after injury. Programmed electric stimulation ex vivo and optical mapping of voltage transients indicated that peptide-treated hearts showed reduced inducible arrhythmias and increased ventricular depolarization rates 7 to 9 days after injury. At 24 hours and 1 week after injury, αCT1-treated hearts maintained Cx43 in intercalated disks (IDs) in the IBZ, whereas by 1 week after injury, controls demonstrated Cx43 remodeling from IDs to lateralized distributions. Over a postinjury time course of 1 week, αCT1-treated IBZs showed increased Cx43 phosphorylation at serine368 (Cx43-pS368) relative to control tissues. In biochemical assays, αCT1 promoted phosphorylation of serine368 by protein kinase (PK)C-ε in a dose-dependent manner that was modulated by, but did not require ZO-1 PDZ2.
  
  
  CONCLUSIONS
  αCT1 increases Cx43-pS368 in vitro in a PKC-ε-dependent manner and in the IBZ in vivo acutely following ventricular injury. αCT1-mediated increase in Cx43-pS368 phosphorylation may contribute to reductions in inducible-arrhythmia following injury.
authors.affiliation: Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: O'Quinn
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Palatinus
authors.forename: Brett S
authors.initials: BS
authors.lastname: Harris
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Hewett
authors.forename: Robert G
authors.initials: RG
authors.lastname: Gourdie
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000517:prevention & control*; D003080:Cold Temperature; D018031:Connexin 43 / Q000737:chemistry* / Q000378:metabolism; D004198:Disease Susceptibility; D004594:Electrophysiology; D005260:Female; D017629:Gap Junctions / Q000187:drug effects*; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006352:Heart Ventricles / Q000293:injuries* / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D051744:Protein Kinase C-epsilon / Q000378:metabolism; D013997:Time Factors; D014018:Tissue Distribution / Q000187:drug effects
chemical_list: D018031:Connexin 43; D010455:Peptides; D051744:Protein Kinase C-epsilon