| A peptide mimetic of the connexin43 carboxyl terminus reduces gap junction remodeling and induced arrhythmia following ventricular injury. | |
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MedLine Citation:
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PMID: 21273554 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Michael P O'Quinn; Joseph A Palatinus; Brett S Harris; Kenneth W Hewett; Robert G Gourdie |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2011-01-27 |
Journal Detail:
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Title: Circulation research Volume: 108 ISSN: 1524-4571 ISO Abbreviation: Circ. Res. Publication Date: 2011 Mar |
Date Detail:
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Created Date: 2011-03-18 Completed Date: 2011-05-23 Revised Date: 2013-01-21 |
Medline Journal Info:
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Nlm Unique ID: 0047103 Medline TA: Circ Res Country: United States |
Other Details:
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Languages: eng Pagination: 704-15 Citation Subset: IM |
Affiliation:
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Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Arrhythmias, Cardiac / etiology, prevention & control* Cold Temperature Connexin 43 / chemistry*, metabolism Disease Susceptibility Electrophysiology Female Gap Junctions / drug effects* Heart / drug effects, physiopathology Heart Ventricles / injuries*, pathology Mice Mice, Inbred Strains Peptides / chemistry*, pharmacology* Phosphorylation / drug effects Protein Kinase C-epsilon / metabolism Time Factors Tissue Distribution / drug effects |
| Grant Support | |
ID/Acronym/Agency:
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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 DE019355-01A2/DE/NIDCR NIH HHS; R01 DE019355-03/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 HL082802-01/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 |
| Chemical | |
Reg. No./Substance:
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0/Connexin 43; 0/Peptides; EC 2.7.11.13/Protein Kinase C-epsilon |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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