Cargando…

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

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Hegner, Philipp, Lebek, Simon, Schaner, Benedikt, Ofner, Florian, Gugg, Mathias, Maier, Lars Siegfried, Arzt, Michael, Wagner, Stefan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9952298/
https://www.ncbi.nlm.nih.gov/pubmed/36829874
http://dx.doi.org/10.3390/antiox12020315
_version_ 1784893596108849152
author Hegner, Philipp
Lebek, Simon
Schaner, Benedikt
Ofner, Florian
Gugg, Mathias
Maier, Lars Siegfried
Arzt, Michael
Wagner, Stefan
author_facet Hegner, Philipp
Lebek, Simon
Schaner, Benedikt
Ofner, Florian
Gugg, Mathias
Maier, Lars Siegfried
Arzt, Michael
Wagner, Stefan
author_sort Hegner, Philipp
collection PubMed
description 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.
format Online
Article
Text
id pubmed-9952298
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-99522982023-02-25 CaMKII-Dependent Contractile Dysfunction and Pro-Arrhythmic Activity in a Mouse Model of Obstructive Sleep Apnea Hegner, Philipp Lebek, Simon Schaner, Benedikt Ofner, Florian Gugg, Mathias Maier, Lars Siegfried Arzt, Michael Wagner, Stefan Antioxidants (Basel) Article 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. MDPI 2023-01-29 /pmc/articles/PMC9952298/ /pubmed/36829874 http://dx.doi.org/10.3390/antiox12020315 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Hegner, Philipp
Lebek, Simon
Schaner, Benedikt
Ofner, Florian
Gugg, Mathias
Maier, Lars Siegfried
Arzt, Michael
Wagner, Stefan
CaMKII-Dependent Contractile Dysfunction and Pro-Arrhythmic Activity in a Mouse Model of Obstructive Sleep Apnea
title CaMKII-Dependent Contractile Dysfunction and Pro-Arrhythmic Activity in a Mouse Model of Obstructive Sleep Apnea
title_full CaMKII-Dependent Contractile Dysfunction and Pro-Arrhythmic Activity in a Mouse Model of Obstructive Sleep Apnea
title_fullStr CaMKII-Dependent Contractile Dysfunction and Pro-Arrhythmic Activity in a Mouse Model of Obstructive Sleep Apnea
title_full_unstemmed CaMKII-Dependent Contractile Dysfunction and Pro-Arrhythmic Activity in a Mouse Model of Obstructive Sleep Apnea
title_short CaMKII-Dependent Contractile Dysfunction and Pro-Arrhythmic Activity in a Mouse Model of Obstructive Sleep Apnea
title_sort camkii-dependent contractile dysfunction and pro-arrhythmic activity in a mouse model of obstructive sleep apnea
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9952298/
https://www.ncbi.nlm.nih.gov/pubmed/36829874
http://dx.doi.org/10.3390/antiox12020315
work_keys_str_mv AT hegnerphilipp camkiidependentcontractiledysfunctionandproarrhythmicactivityinamousemodelofobstructivesleepapnea
AT lebeksimon camkiidependentcontractiledysfunctionandproarrhythmicactivityinamousemodelofobstructivesleepapnea
AT schanerbenedikt camkiidependentcontractiledysfunctionandproarrhythmicactivityinamousemodelofobstructivesleepapnea
AT ofnerflorian camkiidependentcontractiledysfunctionandproarrhythmicactivityinamousemodelofobstructivesleepapnea
AT guggmathias camkiidependentcontractiledysfunctionandproarrhythmicactivityinamousemodelofobstructivesleepapnea
AT maierlarssiegfried camkiidependentcontractiledysfunctionandproarrhythmicactivityinamousemodelofobstructivesleepapnea
AT arztmichael camkiidependentcontractiledysfunctionandproarrhythmicactivityinamousemodelofobstructivesleepapnea
AT wagnerstefan camkiidependentcontractiledysfunctionandproarrhythmicactivityinamousemodelofobstructivesleepapnea