Aims Na+-activated Slack potassium (K+) channels are increasingly recognized as regulators of neuronal activity, yet little is known about their role in the cardiovascular system. Slack activity increases when intracellular Na+ concentration ([Na+]i) reaches pathophysiological levels. Elevated [Na+]i is a major determinant of the ischaemia and reperfusion (I/R)-induced myocardial injury; thus, we hypothesized that Slack plays a role under these conditions. Methods and results K+ currents in cardiomyocytes (CMs) obtained from wildtype but not from global Slack knockout mice were sensitive to electrical inactivation of voltage-sensitive Na+ channels. Live-cell imaging demonstrated that K+ fluxes across the sarcolemma rely on Slack, while the depolarized resting membrane potential in Slack-deficient CMs led to excessive cytosolic Ca2+ accumulation and finally to hypoxia/reoxygenation-induced cell death. Cardiac damage in an in vivo model of I/R was exacerbated in global and CM-specific conditional Slack mutants and largely insensitive to mechanical conditioning manoeuvres. Finally, the protection conferred by mitochondrial ATP-sensitive K+ (mitoKATP) channels required functional Slack in CMs. Conclusion Collectively, our study provides evidence for Slack's crucial involvement in the ion homeostasis of no or low O2-stressed CMs. Thereby, Slack activity opposes the I/R-induced fatal Ca2+-uptake to CMs supporting the cardioprotective signaling attributed to mitoKATP function.

中文翻译：

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松弛 K+ 通道可防止心肌缺血/再灌注损伤


目的 Na+ 激活的松弛钾 （K+） 通道越来越被认为是神经元活动的调节因子，但人们对它们在心血管系统中的作用知之甚少。当细胞内 Na+ 浓度 （[Na+]i） 达到病理生理水平时，松弛活性增加。[Na+]i 升高是缺血和再灌注 （I/R） 诱导的心肌损伤的主要决定因素;因此，我们假设 Slack 在这些情况下起着作用。方法和结果从野生型而非整体 Slack 敲除小鼠获得的心肌细胞 （CMs） 中的 K+ 电流对电压敏感的 Na + 通道的电失活敏感。活细胞成像表明，肌膜上的 K+ 通量依赖于 Slack，而 Slack 缺陷型 CM 中的去极化静息膜电位导致胞质 Ca2+ 过度积累，最终导致缺氧/复氧诱导的细胞死亡。I/R 体内模型中的心脏损伤在全局和 CM 特异性条件 Slack 突变体中加剧，并且在很大程度上对机械调节操作不敏感。最后，线粒体 ATP 敏感 K+ （mitoKATP） 通道赋予的保护需要 CM 中的功能性松弛。结论 总的来说，我们的研究为 Slack 在无 O2 应激或低 O2 应激 CM 的离子稳态中的关键参与提供了证据。因此，Slack 活性反对 I/R 诱导的致命 Ca2+ 摄取对 CM 的致命 Ca2+ 摄取，支持归因于 mitoKATP 功能的心脏保护信号。