Abstract：
OBJECTIVE: 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 ischemia 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 (WT) but not from global Slack knockout (KO) 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 maneuvers. Finally, the protection conferred by mitochondrial ATP-dependent K+ channels required functional Slack in CMs.
CONCLUSIONS: 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 widely attributed to mitoKATP function.
METHODS: and results: K+ currents in cardiomyocytes (CMs) obtained from wildtype (WT) but not from global Slack knockout (KO) 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 maneuvers. Finally, the protection conferred by mitochondrial ATP-dependent K+ channels required functional Slack in CMs.
CONCLUSIONS: 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 widely attributed to mitoKATP function.
摘要：
目的：Na+激活的Slack钾（K+）通道越来越被认为是神经元活动的调节因子，然而，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升高是缺血再灌注(I/R)引起的心肌损伤的主要决定因素,因此，我们假设Slack在这些条件下发挥作用。
方法：和结果：从野生型（WT）但不从全局Slack敲除（KO）小鼠获得的心肌细胞（CM）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，穿过sarcoemma的K通量依赖于Slack，而Slack缺陷型CM中去极化的静息膜电位导致过多的胞浆Ca2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特异性条件性Slack突变体中加剧，并且对机械调节操作不敏感。最后,线粒体ATP依赖性K+通道赋予的保护作用需要CMs的功能性松弛。
结论：总的来说，我们的研究为Slack在无或低O2应激CM的离子稳态中的关键参与提供了证据。因此，松弛活性与I/R诱导的对支持广泛归因于mitoKATP功能的心脏保护性信号传导的CM的致命性Ca2+摄取相反。
方法：和结果：从野生型（WT）但不从全局Slack敲除（KO）小鼠获得的心肌细胞（CM）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，穿过sarcoemma的K通量依赖于Slack，而Slack缺陷型CM中去极化的静息膜电位导致过多的胞浆Ca2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特异性条件性Slack突变体中加剧，并且对机械调节操作不敏感。最后,线粒体ATP依赖性K+通道赋予的保护作用需要CMs的功能性松弛。
结论：总的来说，我们的研究为Slack在无或低O2应激CM的离子稳态中的关键参与提供了证据。因此，松弛活性与I/R诱导的对支持广泛归因于mitoKATP功能的心脏保护性信号传导的CM的致命性Ca2+摄取相反。
