Hegner Philipp, Ofner Florian, Schaner Benedikt, Gugg Mathias, Trum Maximilian, Lauerer Anna-Maria, Maier Lars Siegfried, Arzt Michael, Lebek Simon, Wagner Stefan
Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany.
Department of Neurology and Clinical Neurophysiology, University Hospital Augsburg, Augsburg, Germany.
Front Pharmacol. 2024 Jun 20;15:1411822. doi: 10.3389/fphar.2024.1411822. eCollection 2024.
Obstructive sleep apnea (OSA) has been linked to various pathologies, including arrhythmias such as atrial fibrillation. Specific treatment options for OSA are mainly limited to symptomatic approaches. We previously showed that increased production of reactive oxygen species (ROS) stimulates late sodium current through the voltage-dependent Na channels via Ca/calmodulin-dependent protein kinase IIδ (CaMKIIδ), thereby increasing the propensity for arrhythmias. However, the impact on atrial intracellular Na homeostasis has never been demonstrated. Moreover, the patients often exhibit a broad range of comorbidities, making it difficult to ascertain the effects of OSA alone.
We analyzed the effects of OSA on ROS production, cytosolic Na level, and rate of spontaneous arrhythmia in atrial cardiomyocytes isolated from an OSA mouse model free from comorbidities.
OSA was induced in C57BL/6 wild-type and CaMKIIδ-knockout mice by polytetrafluorethylene (PTFE) injection into the tongue. After 8 weeks, their atrial cardiomyocytes were analyzed for cytosolic and mitochondrial ROS production via laser-scanning confocal microscopy. Quantifications of the cytosolic Na concentration and arrhythmia were performed by epifluorescence microscopy.
PTFE treatment resulted in increased cytosolic and mitochondrial ROS production. Importantly, the cytosolic Na concentration was dramatically increased at various stimulation frequencies in the PTFE-treated mice, while the CaMKIIδ-knockout mice were protected. Accordingly, the rate of spontaneous Ca release events increased in the wild-type PTFE mice while being impeded in the CaMKIIδ-knockout mice.
Atrial Na concentration and propensity for spontaneous Ca release events were higher in an OSA mouse model in a CaMKIIδ-dependent manner, which could have therapeutic implications.
阻塞性睡眠呼吸暂停（OSA）与多种病理状况相关，包括心房颤动等心律失常。OSA的具体治疗选择主要限于对症治疗方法。我们之前表明，活性氧（ROS）生成增加通过钙/钙调蛋白依赖性蛋白激酶IIδ（CaMKIIδ）刺激电压依赖性钠通道的晚期钠电流，从而增加心律失常的倾向。然而，对心房细胞内钠稳态的影响从未得到证实。此外，患者通常表现出广泛的合并症，使得难以确定单独OSA的影响。
我们分析了OSA对从无合并症的OSA小鼠模型分离的心房心肌细胞中ROS生成、胞质钠水平和自发性心律失常发生率的影响。
通过向C57BL/6野生型和CaMKIIδ基因敲除小鼠的舌头注射聚四氟乙烯（PTFE）诱导OSA。8周后，通过激光扫描共聚焦显微镜分析它们的心房心肌细胞的胞质和线粒体ROS生成。通过落射荧光显微镜对胞质钠浓度和心律失常进行定量分析。
PTFE处理导致胞质和线粒体ROS生成增加。重要的是，在PTFE处理的小鼠中，在各种刺激频率下胞质钠浓度显著增加，而CaMKIIδ基因敲除小鼠受到保护。因此，野生型PTFE小鼠中自发性钙释放事件的发生率增加而在CaMKIIδ基因敲除小鼠中受到抑制。
在OSA小鼠模型中，心房钠浓度和自发性钙释放事件的倾向以CaMKIIδ依赖性方式更高，这可能具有治疗意义。
