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Cellular mechanisms of cardioprotection by ischemic preconditioning : Functional study using Kir6.2- (Kir6.2^<-/->) and Kir6.1-deficient (Kir6.1^<-/->) mice

缺血预处理心脏保护的细胞机制：使用 Kir6.2- (Kir6.2^<-/->) 和 Kir6.1 缺陷 (Kir6.1^<-/->) 小鼠进行功能研究

基本信息

批准号：
13670080
负责人：
NAKAYA Haruaki
金额：
$ 2.62万
依托单位：
CHIBA UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

项目摘要

In order to clarify the pathophysiological roles of sarcolemmal ATP-sensitive K^+ (sarcK_<ATP>) channel in cardiac and vascular smooth muscle cells, we conducted functional experiments using Kir6.2-deficient (Kir6.2^<-/->) and Kir6.1-deficient (Kir6.1^<-/->) mice.In ventricular cells of Kir6.2^<-/-> mice sarcK_<ATP> channel function was negated but the mitochondrial K_<ATP> (mitoK_<ATP>) channel function, evaluated by diazoxide-induced flavoprotein oxidation, was preserved. For ischemic preconditioning (IPC) experiments coronary artery was occluded for three periods of 3 min, each followed by 5 min reperfusion, before the long-term ischemia (45 min) in anesthetized mice. IPC reduced the infarct size in wild-type (WT) mice but not in Kir6.2^<-/-> mice. The recovery of the left ventricular contractile function after global ischemia/reperfusion was worse in Langendorff-perfused hearts of Kir6.2^<-/-> mice than in WT hearts. These findings indicate that sarcK_<ATP> channel is important for the establishment of ischemic preconditioning and the recovery of mechanical function after ischemia/reperfusion.We also evaluated sarcK_<ATP> channel function in cardiac and vascular smooth muscle cells of Kir6.1^<-/-> mice. Although both sarcK_<ATP> and mitoK_<ATP> channel function were preserved in cardiac cells of Kir6.1^<-/-> mice, functional responses of sarcK_<ATP> channels to K^+ channel openers were impaired in vascular smooth muscle cells of Kir6.1^<-/-> mice. Of particular interest are the findings that Kir6.2^<-/-> mice showed a high rate of sudden cardiac death associated with spontaneous ST elevation followed by atrioventricular block on ECG. These results suggest that Kir6.1 is critical in the regulation of vascular tone, especially in the coronary arteries, and the dysfunction of the K_<ATP> channel causes Prinzmetal angina.Thus, either Kir6.2 or Kir6.1 is absolutely important for the function of sarcK_<ATP> channels in the cardiovascular system.

为了阐明肌膜ATP敏感性钾通道在心肌和血管平滑肌细胞中的病理生理作用，我们用Kir6.2缺陷(Kir6.2；-/-)和Kir6.1缺陷(Kir6.1；-/-&gt；)小鼠进行了功能实验。在Kir6.2；-/-和kir6.1-/-&gt；小鼠心肌细胞中，线粒体K_&lt；ATP&gt；(mitoK&lt；ATP&gt；))通道功能，以二氮卓诱导的黄素蛋白氧化来评估。在缺血预适应(IPC)实验中，在麻醉小鼠长时间缺血(45min)之前，阻断冠状动脉3次，每次3min，然后再灌流5min。IPC可减少野生型(WT)小鼠的脑梗塞范围，但对Kir6.2^&lt；-/-&gt；小鼠无影响。Kir6.2&lt；-/-&gt；-/-&gt；小鼠全心缺血/再灌流后左室收缩功能的恢复较WT心脏差。这些结果表明，sarcK_lt；ATP&gt；通道在建立缺血预适应和恢复缺血/再灌流后的机械功能中起重要作用。尽管Kir6.1^&lt；-/-&gt；-/-&gt；小鼠心肌细胞sarcK_&lt；ATP&gt；和mitoK_&lt；ATP&gt；通道功能均受到保护，但kir6.1^&lt；-/-&gt；小鼠血管平滑肌细胞对K~+通道开放剂的功能反应受损。特别令人感兴趣的发现是，Kir6.2；&lt；-/-&gt；小鼠在心电图上显示出与自发ST段抬高和房室传导阻滞相关的高心脏性猝死率。这些结果表明，Kir6.1在血管张力调节中起关键作用，尤其是在冠状动脉中，K_lt；ATP&gt；通道的功能障碍会引起血管紧张性心绞痛。因此，Kir6.2或Kir6.1在心血管系统中对sarcK_lt；ATP&gt；通道的功能是绝对重要的。