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.

为了阐明心肌ATP敏感性K^+（sarcK_<ATP>）通道在心脏和血管平滑肌细胞中的病理生理作用，我们利用Kir6.2缺陷型（Kir6.2^<-/-> ）和Kir6.1缺陷型（Kir6.1^<-/->）小鼠。Kir6.2^<-/->小鼠心室细胞中sarcK_<ATP>通道功能被消除，但通过二氮嗪诱导的黄素蛋白氧化评估的线粒体 K_<ATP> (mitoK_<ATP>) 通道功能被保留。对于缺血预适应 (IPC) 实验，在麻醉小鼠中进行长期缺血（45 分钟）之前，将冠状动脉闭塞三个阶段，每次 3 分钟，然后再灌注 5 分钟。 IPC 减少了野生型 (WT) 小鼠的梗塞面积，但没有减少 Kir6.2^</-/-> 小鼠的梗塞面积。 Kir6.2^<-/-> 小鼠 Langendorff 灌注心脏在整体缺血/再灌注后左心室收缩功能的恢复比 WT 心脏更差。这些结果表明sarcK_<ATP>通道对于缺血预处理的建立和缺血/再灌注后机械功能的恢复具有重要意义。我们还评估了Kir6.1^<心脏和血管平滑肌细胞中sarcK_<ATP>通道的功能。 -/-> 老鼠。尽管Kir6.1^</-/->小鼠心肌细胞中sarcK_<ATP>和mitoK_<ATP>通道功能得以保留，但血管平滑肌中sarcK_<ATP>通道对K^+通道开放剂的功能反应受损Kir6.1^</-/-> 小鼠的细胞。特别令人感兴趣的是Kir6.2^-/-小鼠的心源性猝死率很高，其与自发性ST段抬高随后在心电图上出现房室传导阻滞相关。这些结果表明Kir6.1对于血管张力的调节至关重要，尤其是在冠状动脉中，K_<ATP>通道的功能障碍会导致Prinzmetal心绞痛。因此，Kir6.2或Kir6.1对于调节血管紧张度绝对重要。心血管系统中sarcK_<ATP>通道的功能。