Structural and molecular mechanisms of gap junction remodeling in epicardial border zone myocytes following myocardial infarction

Fabien Kieken, Nancy Mutsaers, Elena Dolmatova, Kelly Virgil, Andrew L. Wit, Admir Kellezi, Bethany J. Hirst-Jensen, Heather S. Duffy, Paul L. Sorgen

Research output: Contribution to journalArticle

94 Citations (Scopus)

Abstract

Lateralization of the ventricular gap junction protein connexin 43 (Cx43) occurs in epicardial border zone myocytes following myocardial infarction (MI) and is arrhythmogenic. Alterations in Cx43 protein partners have been hypothesized to play a role in lateralization although mechanisms by which this occurs are unknown. To examine potential mechanisms we did nuclear magnetic resonance, yeast 2-hybrid, and surface plasmon resonance studies and found that the SH3 domain of the tyrosine kinase c-Src binds to the Cx43 scaffolding protein zonula occludens-1 (ZO-1) with a higher affinity than does Cx43. This suggests c-Src outcompetes Cx43 for binding to ZO-1, thus acting as a chaperone for ZO-1 and causing unhooking from Cx43. To determine whether c-Src/ZO-1 interactions affect Cx43 lateralization within the epicardial border zone, we performed Western blot, immunoprecipitation, and immunolocalization for active c-Src (p-cSrc) post-MI using a canine model of coronary occlusion. We found that post-MI p-cSrc interacts with ZO-1 as Cx43 begins to decrease its interaction with ZO-1 and undergo initial loss of intercalated disk localization. This indicates that the molecular mechanisms by which Cx43 is lost from the intercalated disk following MI includes an interaction of p-cSrc with ZO-1 and subsequent loss of scaffolding of Cx43 leaving Cx43 free to diffuse in myocyte membranes from areas of high Cx43, as at the intercalated disk, to regions of lower Cx43 content, the lateral myocyte membrane. Therefore shifts in Cx43 protein partners may underlie, in part, arrhythmogenesis in the post-MI heart.

Original languageEnglish (US)
Pages (from-to)1103-1112
Number of pages10
JournalCirculation Research
Volume104
Issue number9
DOIs
StatePublished - May 8 2009
Externally publishedYes

Fingerprint

Connexin 43
Gap Junctions
Muscle Cells
Myocardial Infarction
Tight Junctions
Zonula Occludens-1 Protein
Connexins
src Homology Domains
Membranes
Surface Plasmon Resonance
Coronary Occlusion
Immunoprecipitation
Protein-Tyrosine Kinases
Canidae

Keywords

  • Arrhythmia
  • Cardiac gap junction connexins
  • Cell' cell coupling
  • Myocardial ischemia

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Structural and molecular mechanisms of gap junction remodeling in epicardial border zone myocytes following myocardial infarction. / Kieken, Fabien; Mutsaers, Nancy; Dolmatova, Elena; Virgil, Kelly; Wit, Andrew L.; Kellezi, Admir; Hirst-Jensen, Bethany J.; Duffy, Heather S.; Sorgen, Paul L.

In: Circulation Research, Vol. 104, No. 9, 08.05.2009, p. 1103-1112.

Research output: Contribution to journalArticle

Kieken, F, Mutsaers, N, Dolmatova, E, Virgil, K, Wit, AL, Kellezi, A, Hirst-Jensen, BJ, Duffy, HS & Sorgen, PL 2009, 'Structural and molecular mechanisms of gap junction remodeling in epicardial border zone myocytes following myocardial infarction', Circulation Research, vol. 104, no. 9, pp. 1103-1112. https://doi.org/10.1161/CIRCRESAHA.108.190454
Kieken, Fabien ; Mutsaers, Nancy ; Dolmatova, Elena ; Virgil, Kelly ; Wit, Andrew L. ; Kellezi, Admir ; Hirst-Jensen, Bethany J. ; Duffy, Heather S. ; Sorgen, Paul L. / Structural and molecular mechanisms of gap junction remodeling in epicardial border zone myocytes following myocardial infarction. In: Circulation Research. 2009 ; Vol. 104, No. 9. pp. 1103-1112.
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AU - Mutsaers, Nancy

AU - Dolmatova, Elena

AU - Virgil, Kelly

AU - Wit, Andrew L.

AU - Kellezi, Admir

AU - Hirst-Jensen, Bethany J.

AU - Duffy, Heather S.

AU - Sorgen, Paul L.

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