Role of Kir6.1 channels in cardiomyocytes clarified by Kir6.1-transgenic mice

目前认为，心肌ATP敏感(K&lt；ATP&gt；)通道是由成孔亚基Kir6.2和调节亚单位磺脲受体(SUR2A)组成的异八聚体。尽管据报道在心脏细胞中存在另一个形成孔的亚基Kir6.1，但Kir6.1在心脏中的病理生理学意义尚不清楚。本研究通过在心肌中高表达Kir6.1基因(Kir6.1TG)的转基因小鼠来评价心脏Kir6.1蛋白的作用。将野生型(WT)和Kir6.1TG小鼠的心脏灌流至全脑缺血(25min)后再灌流(120min)。氯化三苯基四氮唑染色显示Kir6.1Tg组心肌梗死面积小于WT组，收缩功能恢复较WT组大。在Kir6.1TG小鼠冠脉灌流的心肌标本中，缺血前的动作电位时程比WT制剂的动作电位时程长，可能与K~+通道下调有关。在缺血期间，Kir6.1Tg制剂的动作电位时程缩短加快。用二氮嗪诱导的黄素蛋白氧化间接评价Kir6.1TG和WT心肌细胞线粒体K_lt；ATP&gt；通道活性无明显差异。提示心肌细胞Kir6.1蛋白对心肌缺血/再灌注损伤具有保护作用。

It is acknowledged that cardiac ATP-sensitive (K_<ATP>) channel is a hetero-octamer comprising the pore-forming subunit Kir6.2 and the regulatory subunit sulfonylurea receptor (SUR2A). Although another pore-forming subunit Kir6.1 reportedly exists in heart cells, the pathophysiological significance of Kir6.1 in the heart remains unclear. This study was undertaken to evaluate the role of cardiac Kir6.1 protein using transgenic mice overexpressing Kir6.1 gene (Kir6.1TG) in the myocardium. Langendorff-perfused hearts of wild-type (WT) and Kir6.1TG mice were subjected to global ischemia (25 min) followed by reperfusion (120 min). Myocardial infarct size, measured by triphenyltetrazolium chloride staining, in Kir6.1TG hearts was smaller and recovery of contractile function of Kir6.1TG hearts was greater compared with WT hearts. In coronary-perfused ventricular muscle preparations of Kir6.1TG mice, the action potential duration (APD) was longer than that of WT preparations in pre-ischemic period, probably due to downregulation of K^+ channels. During ischemia the APD shortening was accelerated in Kir6.1TG preparations. There was no difference in mitochondrial K_<ATP> channel activity, which was indirectly evaluated by diazoxide-induced flavoprotein oxidation, between Kir6.1TG and WT cardiomyocytes. These findings suggest that Kir6.1 protein in cardiomyocytes affords cardioprotection against ischemia/reperfusion injury.