title: Alterations in connexin 43 during diabetic cardiomyopathy: competition of tyrosine nitration versus phosphorylation.
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.
authors.affiliation: Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne, Victoria 3150, Australia.|Department of Medicine, Central Clinical School, Monash University, Melbourne, Australia.|University of Kentucky College of Medicine, Department of Pediatrics, Lexington KY 40536, USA.
authors.forename: Mandar S
authors.initials: MS
authors.lastname: Joshi
authors.affiliation: The Ohio State University College of Pharmacy, 500 W 12 Ave, Columbus, OH 43210, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Mihm
authors.affiliation: The Ohio State University College of Pharmacy, 500 W 12 Ave, Columbus, OH 43210, USA.
authors.forename: Angela C
authors.initials: AC
authors.lastname: Cook
authors.affiliation: Centre for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA.|University of Kentucky College of Medicine, Department of Pediatrics, Lexington KY 40536, USA.
authors.forename: Brandon L
authors.initials: BL
authors.lastname: Schanbacher
authors.affiliation: Centre for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA.|University of Kentucky College of Medicine, Department of Pediatrics, Lexington KY 40536, USA.
authors.forename: John Anthony
authors.initials: JA
authors.lastname: Bauer
mesh_terms: D000818:Animals; D015153:Blotting, Western; D018031:Connexin 43 / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D058065:Diabetic Cardiomyopathies / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D004594:Electrophysiology; D006943:Hyperglycemia / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D008297:Male; D009584:Nitrogen / Q000378:metabolism*; D018384:Oxidative Stress; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D014443:Tyrosine / Q000378:metabolism*
chemical_list: D018031:Connexin 43; D014443:Tyrosine; D009584:Nitrogen
keywords: cardiomyopathy; connexins; diabetes; oxidative stress; signal transduction; 关键词：心肌病，间隙连接蛋白，糖尿病，氧化应激，信号转导