Joshi Mandar S, Mihm Michael J, Cook Angela C, Schanbacher Brandon L, Bauer John Anthony
Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne, Victoria 3150, Australia.
Department of Medicine, Central Clinical School, Monash University, Melbourne, Australia.
J Diabetes. 2015 Mar;7(2):250-259. doi: 10.1111/1753-0407.12164. Epub 2014 Jul 15.
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.
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.
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.
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.
在1型糖尿病（T1D）进展过程中可早期观察到心脏传导异常，但相关机制尚不明确。连接蛋白43是心室间隙连接的关键成分，其通过酪氨酸磷酸化状态来调节通道电导；连接蛋白43的含量、分布和/或磷酸化状态的改变可能与心律失常有关。我们检验了这样一个假设，即在T1D心肌病大鼠模型中连接蛋白43的心脏含量和/或分布发生改变，并研究酪氨酸的机制性作用。
在糖尿病诱导后3天、7天和35天给大鼠注射链脲佐菌素（STZ；65mg/kg），在糖尿病性心肌病进展过程中进行心电图分析。在功能分析之后，我们进行免疫组织化学和免疫沉淀研究以评估连接蛋白43的改变。
早在STZ注射后7天就有明显的心室传导异常（QRS波群、Q-T间期）证据，且在整个研究过程中持续存在。STZ注射后7天连接蛋白43水平升高，并在整个研究过程中保持升高。在整个研究过程中，连接蛋白40含量相对于对照组没有变化。还观察到连接蛋白43分布的改变：连接蛋白43染色从心肌细胞短轴连接处分散。在糖尿病进展过程中，连接蛋白43酪氨酸磷酸化下降，同时酪氨酸硝化增加。
数据表明，在实验性糖尿病期间连接蛋白43的含量和分布发生变化，可能导致心脏功能改变，并且酪氨酸介导的信号的氧化修饰可能起机制性作用。
