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

作者：Joshi Mandar S; Mihm Michael J; Cook Angela C; Schanbacher Brandon L; Bauer John Anthony^*

来源：Journal of Diabetes, 2015, 7(2): 250-259.

DOI：10.1111/1753-0407.12164

• cardiomyopathy
• connexins
• diabetes
• oxidative stress
• signal transduction

BackgroundCardiac 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.
MethodsElectrocardiographic 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.
ResultsThere 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.
ConclusionsThe 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.

• 出版日期2015-3