Mitochondrial ATP-dependent potassium channels - Novel effectors of cardioprotection?
Mitochondrial ATP-dependent potassium channels - Novel effectors of cardioprotection?
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DOI：
10.1161/01.cir.97.24.2463
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发表时间：
1998-06-23
期刊：
影响因子：
37.8
通讯作者：
Marban, E
中科院分区：
文献类型：
--
作者：
Liu, YG;Sato, T;Marban, E
背景：冠状动脉血流的短暂中断矛盾地保护心脏免受随后的长时间缺血。这种内源性心脏保护的基础，被称为“缺血预处理”，仍然不确定。药理学证据表明atp依赖性钾（K-ATP）通道参与了预处理机制；然而，肌层K-ATP通道对兴奋性的影响并不能解释这种保护作用。方法和结果-我们同时测量了完整兔心室肌细胞的黄蛋白荧光、线粒体氧化还原状态指数和肌层K-ATP电流。我们的结果表明，二氮氧化物是一种K-ATP通道打开剂，可以选择性地激活线粒体K-ATP通道。二氮氧化合物诱导黄蛋白可逆氧化，EC为27 μ mol/L，但不激活肌层K-ATP通道。通过黄蛋白和四甲基罗丹明乙酯产生的荧光共聚焦成像，二氮氧化物作用的亚细胞位点进一步定位于线粒体。在模拟缺血的细胞模型中，二氮氧化物的加入使细胞死亡率降低到对照组的一半左右。K-ATP通道阻滞剂5-羟基癸酸可抑制氧化还原变化和保护作用。结论：我们的研究结果表明，二氮氧化物靶向线粒体而非肌层K-ATP通道，这意味着线粒体K-ATP通道可能介导K-ATP通道打开剂的保护作用。
Background-Brief interruptions of coronary blood flow paradoxically protect the heart from subsequent prolonged ischemia. The basis of such endogenous cardioprotection, known as "ischemic preconditioning," remains uncertain. Pharmacological evidence has implicated ATP-dependent potassium (K-ATP) channels in the mechanism of preconditioning; however, the effects of sarcolemmal K-ATP channels on excitability cannot account for the protection.Methods and Results-We simultaneously measured flavoprotein fluorescence, an index of mitochondrial redox state, and sarcolemmal K-ATP currents in intact rabbit ventricular myocytes, Our results show that diazoxide, a K-ATP channel opener, selectively activates mitochondrial K-ATP channels. Diazoxide induced reversible oxidation of flavoproteins with an EC,, of 27 mu mol/L but did not activate sarcolemmal K-ATP channels. The subcellular site of diazoxide action is further localized to mitochondria by confocal imaging of fluorescence arising from flavoproteins and tetramethylrhodamine ethyl eater, In a cellular model of simulated ischemia, inclusion of diazoxide decreased the rate of cell death to about half of that in controls. Both the redox changes and protection are inhibited by the K-ATP channel blocker 5-hydroxydecanoic acid.Conclusions-Our results demonstrate that diazoxide targets mitochondrial but not sarcolemmal K-ATP channels and imply that mitochondrial K-ATP channels may mediate the protection from K-ATP channel openers.