Document Detail

A peptide mimetic of the connexin43 carboxyl terminus reduces gap junction remodeling and induced arrhythmia following ventricular injury.
MedLine Citation:
PMID:  21273554     Owner:  NLM     Status:  MEDLINE    
RATIONALE: Remodeling of connexin (Cx)43 gap junctions (GJs) is linked to ventricular arrhythmia.
OBJECTIVES: 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.
METHODS AND 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.
Michael P O'Quinn; Joseph A Palatinus; Brett S Harris; Kenneth W Hewett; Robert G Gourdie
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-01-27
Journal Detail:
Title:  Circulation research     Volume:  108     ISSN:  1524-4571     ISO Abbreviation:  Circ. Res.     Publication Date:  2011 Mar 
Date Detail:
Created Date:  2011-03-18     Completed Date:  2011-05-23     Revised Date:  2014-09-18    
Medline Journal Info:
Nlm Unique ID:  0047103     Medline TA:  Circ Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  704-15     Citation Subset:  IM    
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MeSH Terms
Arrhythmias, Cardiac / etiology,  prevention & control*
Cold Temperature
Connexin 43 / chemistry*,  metabolism
Disease Susceptibility
Gap Junctions / drug effects*
Heart / drug effects,  physiopathology
Heart Ventricles / injuries*,  pathology
Mice, Inbred Strains
Peptides / chemistry*,  pharmacology*
Phosphorylation / drug effects
Protein Kinase C-epsilon / metabolism
Time Factors
Tissue Distribution / drug effects
Grant Support
F30 HL095320/HL/NHLBI NIH HHS; F30 HL095320/HL/NHLBI NIH HHS; F30 HL095320-01/HL/NHLBI NIH HHS; F30 HL095320-02/HL/NHLBI NIH HHS; F30 HL095320-03/HL/NHLBI NIH HHS; F30 HL095320-04/HL/NHLBI NIH HHS; HL082802/HL/NHLBI NIH HHS; HL56728/HL/NHLBI NIH HHS; R01 DE019355/DE/NIDCR NIH HHS; R01 DE019355-01A2/DE/NIDCR NIH HHS; R01 HL056728/HL/NHLBI NIH HHS; R01 HL056728-03/HL/NHLBI NIH HHS; R01 HL056728-04/HL/NHLBI NIH HHS; R01 HL056728-05/HL/NHLBI NIH HHS; R01 HL056728-06/HL/NHLBI NIH HHS; R01 HL056728-07/HL/NHLBI NIH HHS; R01 HL056728-08/HL/NHLBI NIH HHS; R01 HL056728-09/HL/NHLBI NIH HHS; R01 HL056728-10A2/HL/NHLBI NIH HHS; R01 HL056728-11/HL/NHLBI NIH HHS; R01 HL056728-12/HL/NHLBI NIH HHS; R01 HL082802/HL/NHLBI NIH HHS; R01 HL082802-01/HL/NHLBI NIH HHS; R01 HL082802-02/HL/NHLBI NIH HHS; R01 HL082802-03/HL/NHLBI NIH HHS; R01 HL082802-04/HL/NHLBI NIH HHS; T32 HL007260/HL/NHLBI NIH HHS
Reg. No./Substance:
0/Connexin 43; 0/Peptides; EC Kinase C-epsilon

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