{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T03:04:13Z","timestamp":1784603053415,"version":"3.55.0"},"reference-count":62,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,6,20]],"date-time":"2024-06-20T00:00:00Z","timestamp":1718841600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>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<jats:sup>+<\/jats:sup> channels via Ca<jats:sup>2+<\/jats:sup>\/calmodulin-dependent protein kinase II\u03b4 (CaMKII\u03b4), thereby increasing the propensity for arrhythmias. However, the impact on atrial intracellular Na<jats:sup>+<\/jats:sup> 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>We analyzed the effects of OSA on ROS production, cytosolic Na<jats:sup>+<\/jats:sup> level, and rate of spontaneous arrhythmia in atrial cardiomyocytes isolated from an OSA mouse model free from comorbidities.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>OSA was induced in C57BL\/6 wild-type and CaMKII\u03b4-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<jats:sup>+<\/jats:sup> concentration and arrhythmia were performed by epifluorescence microscopy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>PTFE treatment resulted in increased cytosolic and mitochondrial ROS production. Importantly, the cytosolic Na<jats:sup>+<\/jats:sup> concentration was dramatically increased at various stimulation frequencies in the PTFE-treated mice, while the CaMKII\u03b4-knockout mice were protected. Accordingly, the rate of spontaneous Ca<jats:sup>2+<\/jats:sup> release events increased in the wild-type PTFE mice while being impeded in the CaMKII\u03b4-knockout mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Atrial Na<jats:sup>+<\/jats:sup> concentration and propensity for spontaneous Ca<jats:sup>2+<\/jats:sup> release events were higher in an OSA mouse model in a CaMKII\u03b4-dependent manner, which could have therapeutic implications.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fphar.2024.1411822","type":"journal-article","created":{"date-parts":[[2024,6,20]],"date-time":"2024-06-20T05:11:38Z","timestamp":1718860298000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["CaMKII\u03b4-dependent dysregulation of atrial Na+ homeostasis promotes pro-arrhythmic activity in an obstructive sleep apnea mouse model"],"prefix":"10.3389","volume":"15","author":[{"given":"Philipp","family":"Hegner","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian","family":"Ofner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benedikt","family":"Schaner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathias","family":"Gugg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maximilian","family":"Trum","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna-Maria","family":"Lauerer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars Siegfried","family":"Maier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Arzt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Lebek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Wagner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,6,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1454","DOI":"10.1172\/JCI70420","article-title":"Obstructive sleep apnea and insight into mechanisms of sympathetic overactivity","volume":"124","author":"Abboud","year":"2014","journal-title":"J. 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