Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido , Japan.
Department of Molecular Biology, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido , Japan.
Am J Physiol Heart Circ Physiol. 2018 Aug 1;315(2):H262-H272. doi: 10.1152/ajpheart.00636.2017. Epub 2018 Apr 6.
The molecular and electrophysiological mechanisms of acute ischemic ventricular arrhythmias in hypertrophied hearts are not well known. We hypothesized that small-conductance Ca-activated K (SK) channels are activated during hypoxia via the Ca/calmodulin-dependent protein kinase II (CaMKII)-dependent pathway. We used normotensive Wistar-Kyoto (WKY) rats and spontaneous hypertensive rats (SHRs) as a model of cardiac hypertrophy. The inhibitory effects of SK channels and ATP-sensitive K channels on electrophysiological changes and genesis of arrhythmias during simulated global hypoxia (GH) were evaluated. Hypoxia-induced abbreviation of action potential duration (APD) occurred earlier in ventricles from SHRs versus. WKY rats. Apamin, a SK channel blocker, prevented this abbreviation in SHRs in both the early and delayed phase of GH, whereas in WKY rats only the delayed phase was prevented. In contrast, SHRs were less sensitive to glibenclamide, a ATP-sensitive K channel blocker, which inhibited the APD abbreviation in both phases of GH in WKY rats. SK channel blockers (apamin and UCL-1684) reduced the incidence of hypoxia-induced sustained ventricular arrhythmias in SHRs but not in WKY rats. Among three SK channel isoforms, SK2 channels were directly coimmunoprecipitated with CaMKII phosphorylated at Thr (p-CaMKII). We conclude that activation of SK channels leads to the APD abbreviation and sustained ventricular arrhythmias during simulated hypoxia, especially in hypertrophied hearts. This mechanism may result from p-CaMKII-bound SK2 channels and reveal new molecular targets to prevent lethal ventricular arrhythmias during acute hypoxia in cardiac hypertrophy. NEW & NOTEWORTHY We now show a new pathophysiological role of small-conductance Ca-activated K channels, which shorten the action potential duration and induce ventricular arrhythmias during hypoxia. We also demonstrate that small-conductance Ca-activated K channels interact with phosphorylated Ca/calmodulin-dependent protein kinase II at Thr in hypertrophied hearts.
急性缺血性心室心律失常在肥厚心脏中的分子和电生理机制尚不清楚。我们假设小电导钙激活钾（SK）通道在缺氧期间通过钙/钙调蛋白依赖性蛋白激酶 II（CaMKII）依赖性途径被激活。我们使用正常血压的 Wistar-Kyoto（WKY）大鼠和自发性高血压大鼠（SHR）作为心脏肥厚模型。评估 SK 通道和 ATP 敏感性钾通道对模拟全球缺氧（GH）期间电生理变化和心律失常发生的抑制作用。与 WKY 大鼠相比，SHR 心室中的缺氧诱导的动作电位持续时间（APD）缩短发生得更早。SK 通道阻滞剂 apamin 可防止 SHR 在 GH 的早期和延迟期发生这种缩短，而在 WKY 大鼠中仅防止延迟期发生。相比之下，SHR 对 glibenclamide 的敏感性较低，后者是一种 ATP 敏感性钾通道阻滞剂，可抑制 WKY 大鼠 GH 的两个阶段的 APD 缩短。SK 通道阻滞剂（apamin 和 UCL-1684）可降低 SHR 中缺氧诱导的持续性室性心律失常的发生率，但在 WKY 大鼠中则没有。在三种 SK 通道亚型中，SK2 通道直接与 Thr 磷酸化的 CaMKII（p-CaMKII）共免疫沉淀。我们得出结论，SK 通道的激活导致模拟缺氧期间 APD 缩短和持续性室性心律失常，尤其是在肥厚的心脏中。这种机制可能源于与 p-CaMKII 结合的 SK2 通道，并揭示了在心脏肥厚期间急性缺氧时防止致命性室性心律失常的新分子靶标。
新的和值得注意的是，我们现在显示小电导钙激活钾通道具有新的病理生理作用，即在缺氧期间缩短动作电位持续时间并诱导室性心律失常。我们还证明在肥厚的心脏中，小电导钙激活钾通道与 Thr 磷酸化的钙/钙调蛋白依赖性蛋白激酶 II 相互作用。
