Mandar S Joshi1,2,3, Michael J Mihm4, Angela C Cook4, Brandon L Schanbacher5,3, John Anthony Bauer5,3. 1. Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne, Victoria 3150, Australia. 2. Department of Medicine, Central Clinical School, Monash University, Melbourne, Australia. 3. University of Kentucky College of Medicine, Department of Pediatrics, Lexington KY 40536, USA. 4. The Ohio State University College of Pharmacy, 500 W 12 Ave, Columbus, OH 43210, USA. 5. Centre for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA.
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; 65 mg/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.
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; 65 mg/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 43tyrosine 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.
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