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

心脏ATP敏感性（K_<ATP>）通道是一个由孔形成亚基Kir6.2和磺酰脲受体调节亚基SUR 2A组成的杂八聚体。虽然另一个成孔亚基Kir6.1存在于心脏细胞中，但Kir6.1在心脏中的病理生理学意义尚不清楚。本研究采用Kir6.1基因过表达转基因小鼠（Kir6.1TG），探讨Kir6.1蛋白在心肌中的作用。对野生型（WT）和Kir6.1TG小鼠的Langendorff灌注心脏进行全脑缺血（25分钟），然后再灌注（120分钟）。与WT心脏相比，Kir6.1TG心脏的心肌梗死面积（通过氯化三苯基四氮唑染色测量）较小，收缩功能恢复更快。在Kir6.1TG小鼠冠状动脉灌注的心室肌标本中，缺血前期动作电位时程（APD）比WT标本长，可能是由于K^+通道下调所致。缺血时，Kir6.1TG使APD缩短加速。Kir6.1TG<ATP>和WT心肌细胞线粒体K通道活性无明显差异。这些结果表明，Kir6.1蛋白在心肌细胞中提供心脏保护对缺血/再灌注损伤。

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.