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

96 Scopus citations

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

Keywords

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

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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    Kieken, F., Mutsaers, N., Dolmatova, E., Virgil, K., Wit, A. L., Kellezi, A., Hirst-Jensen, B. J., Duffy, H. S., & Sorgen, P. L. (2009). Structural and molecular mechanisms of gap junction remodeling in epicardial border zone myocytes following myocardial infarction. Circulation research, 104(9), 1103-1112. https://doi.org/10.1161/CIRCRESAHA.108.190454