CaMKII-Dependent Contractile Dysfunction and Pro-Arrhythmic Activity in a Mouse Model of Obstructive Sleep Apnea

• Published in: Antioxidants Vol. 12; no. 2; p. 315
• Main Authors: Hegner, Philipp, Lebek, Simon, Schaner, Benedikt, Ofner, Florian, Gugg, Mathias, Maier, Lars Siegfried, Arzt, Michael, Wagner, Stefan
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 29.01.2023; MDPI
• Subjects: Ablation; Airway management; Apnea; Arrhythmia; arrhythmias; Ca2+/calmodulin-dependent protein kinase II; Caffeine; CaMKII; Cardiac arrhythmia; Cardiac function; Cardiomyocytes; Cardiovascular research; Comorbidity; contractile dysfunction; Echocardiography; Ejection fraction; Genotype & phenotype; Glucose; Heart; Heart failure; Homeostasis; Kinases; Laboratory animals; Microscopy; Muscle contraction; obstructive sleep apnea; oxidative stress; Reactive oxygen species; Respiration; Sleep apnea; Sleep apnea syndromes; Sleep disorders; Tongue; Ventricle; Germany; Canada; United States > US; obstructive sleep apnea; contractile dysfunction; CaMKII; arrhythmias; oxidative stress
• ISSN: 2076-3921; 2076-3921
• DOI: 10.3390/antiox12020315

Left ventricular contractile dysfunction and arrhythmias frequently occur in patients with sleep-disordered breathing (SDB). The CaMKII-dependent dysregulation of cellular Ca homeostasis has recently been described in SDB patients, but these studies only partly explain the mechanism and are limited by the patients' heterogeneity. Here, we analyzed contractile function and Ca homeostasis in a mouse model of obstructive sleep apnea (OSA) that is not limited by confounding comorbidities. OSA was induced by artificial tongue enlargement with polytetrafluorethylene (PTFE) injection into the tongue of wildtype mice and mice with a genetic ablation of the oxidative activation sites of CaMKII (MMVV knock-in). After eight weeks, cardiac function was assessed with echocardiography. Reactive oxygen species (ROS) and Ca transients were measured using confocal and epifluorescence microscopy, respectively. Wildtype PTFE mice exhibited an impaired ejection fraction, while MMVV PTFE mice were fully protected. As expected, isolated cardiomyocytes from PTFE mice showed increased ROS production. We further observed decreased levels of steady-state Ca transients, decreased levels of caffeine-induced Ca transients, and increased pro-arrhythmic activity (defined as deviations from the diastolic Ca baseline) only in wildtype but not in MMVV PTFE mice. In summary, in the absence of any comorbidities, OSA was associated with contractile dysfunction and pro-arrhythmic activity and the inhibition of the oxidative activation of CaMKII conveyed cardioprotection, which may have therapeutic implications.