Alterations in connexin 43 during diabetic cardiomyopathy: Competition of tyrosine nitration versus phosphorylation

Mandar S. Joshi, Michael J. Mihm, Angela C. Cook, Brandon L. Schanbacher, John Anthony Bauer

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

Background: Cardiac conduction abnormalities are observed early in the progression of type 1 diabetes (T1D), but the mechanism(s) involved are undefined. Connexin 43, a critical component of ventricular gap junctions, depends on tyrosine phosphorylation status to modulate channel conductance; changes in connexin 43 content, distribution, and/or phosphorylation status may be involved in cardiac rhythm disturbances. We tested the hypothesis that cardiac content and/or distribution of connexin 43 is altered in a rat model of T1D cardiomyopathy, investigating a mechanistic role for tyrosine. Methods: Electrocardiographic analyses were conducted during the progression of diabetic cardiomyopathy in rats dosed with streptozotocin (STZ; 65mg/kg) 3, 7, and 35 days after the induction of diabetes. Following functional analyses, we conducted immunohistochemical and immunoprecipitation studies to assess alterations in connexin 43. Results: There was significant evidence of ventricular conduction abnormalities (QRS complex, Q-T interval) as early as 7 days after STZ, persisting throughout the study. Connexin 43 levels were increased 7 days after STZ and remained elevated throughout the study. Connexin 40 content was unchanged relative to controls throughout the study. Changes in connexin 43 distribution were also observed: connexin 43 staining was dispersed from myocyte short axis junctions. Connexin 43 tyrosine phosphorylation declined during the progression of diabetes, with concurrent increases in tyrosine nitration. Conclusions: The data suggest that changes in connexin 43 content and distribution occur during experimental diabetes and likely contribute to alterations in cardiac function, and that oxidative modification of tyrosine-mediated signaling may play a mechanistic role.

Original languageEnglish
Pages (from-to)250-259
Number of pages10
JournalJournal of Diabetes
Volume7
Issue number2
DOIs
StatePublished - Mar 1 2015

Bibliographical note

Publisher Copyright:
© 2014 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd.

Keywords

  • Cardiomyopathy
  • Connexins
  • Diabetes
  • Oxidative stress
  • Signal transduction

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism

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