Diazoxide-induced cardioprotection requires signaling through a redox-sensitive mechanism
Diazoxide-induced cardioprotection requires signaling through a redox-sensitive mechanism
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DOI：
10.1161/hh0801.089342
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发表时间：
2001-04-27
影响因子：
20.1
通讯作者：
Murphy, E
中科院分区：
文献类型：
--
作者：
Forbes, RA;Steenbergen, C;Murphy, E
二氮嗪是线粒体 ATP 敏感钾通道的选择性开放剂，已被证明可引发心肌细胞和灌注心脏对缺血的耐受性。然而，人们对这种心脏保护机制知之甚少。由于活性氧 (ROS) 被认为是重要的细胞内信号分子，并且与缺血预处理有关，因此我们检查了二氮嗪诱导的成年心肌细胞中 ROS 的产生，用 50 μmol/L 二氮嗪处理的细胞显示 ROS 产生相对于基线增加了 173%。研究发现 5-Hydroxydecanoate 可减弱二氮嗪诱导的 ROS 生成增加。添加抗氧化剂 N-乙酰半胱氨酸 (NAC) 或 N-巯基丙酰甘氨酸也可以消除二氮嗪诱导的 ROS 增加。我们还检查了 NAC 阻断二氮嗪对灌注大鼠心脏的保护作用的能力。经过20分钟的整体缺血和20分钟的复流后，缺血前用100μmol/L二氮嗪灌注的心脏相对于未治疗的心脏表现出显着改善的缺血后收缩功能（分别为初始左心室发展压力的84％和29％）。在 4 mmol/L NAC 存在下，用二氮嗪治疗的心脏恢复了 53% 的初始左心室发展压力，而仅用 NAC 治疗的心脏则恢复了 46% 的缺血前功能。使用 P-31 NMR 光谱，我们发现，与预处理类似，二氮嗪显着减弱缺血诱导的细胞内酸化并增强磷酸肌酸水平的缺血后恢复，而这两种情况均被 NAG 联合治疗所阻断。这些数据表明二氮嗪的心脏保护作用是通过促氧化环境的产生介导的。
Diazoxide, a selective opener of the mitochondrial ATP-sensitive potassium channel, has been shown to elicit tolerance to ischemia in cardiac myocytes and in perfused heart. However, the mechanism of this cardioprotection is poorly understood. Because reactive oxygen species (ROS) are recognized as important intracellular signaling molecules and have been implicated in ischemic preconditioning, we examined diazoxide-induced ROS production in adult cardiomyocytes, Cells treated with 50 mu mol/L diazoxide showed a 173% increase in ROS production relative to baseline. 5-Hydroxydecanoate was found to attenuate the diazoxide-induced increase in ROS generation. The diazoxide-induced increase in ROS also was abrogated by the addition of either the antioxidant N-acetylcysteine (NAC) or N-mercaptopropionylglycine. We also examined the ability of NAC to block the protective effects of diazoxide in the perfused rat heart. After 20 minutes of global ischemia and 20 minutes of reflow, hearts perfused with 100 mu mol/L diazoxide before ischemia showed significantly improved postischemic contractile function relative to untreated hearts (84% versus 29% of initial left ventricular developed pressure, respectively). Hearts treated with diazoxide in the presence of 4 mmol/L NAC recovered 53% of initial left ventricular developed pressure, whereas hearts treated with NAC alone recovered 46% of preischemic function. Using P-31 NMR spectroscopy, we found that, similar to preconditioning, diazoxide significantly attenuated ischemia-induced intracellular acidification and enhanced postischemic recovery of phosphocreatine levels, both of which were blocked by cotreatment with NAG. These data suggest that the cardioprotective actions of diazoxide are mediated by generation of a pro-oxidant environment.