Obstructive Sleep Apnea Syndrome In Vitro Model: Controlled Intermittent Hypoxia Stimulation of Human Stem Cells-Derived Cardiomyocytes

Cardiovascular morbidity is the leading cause of death of obstructive sleep apnea (OSA) syndrome patients. Nocturnal airway obstruction is associated with intermittent hypoxia (IH). In our previous work with cell lines, incubation with sera from OSA patients induced changes in cell morphology, NF-κB...

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Bibliographic Details
Published in:International journal of molecular sciences 2022-09, Vol.23 (18), p.10272
Main Authors: Regev, Danielle, Etzion, Sharon, Haddad, Hen, Gopas, Jacob, Goldbart, Aviv
Format: Article
Language:English
Subjects:
Apnea
Calcium (intracellular)
Calcium signalling
Cardiomyocytes
Cardiovascular disease
Cell activation
Cell differentiation
Cell lines
Cytokines
Cytology
Embryo cells
hESC-CM
Hypoxia
Hypoxia-inducible factor 1a
Inflammation
intermittent hypoxia
Intracellular signalling
Laboratories
Monocyte chemoattractant protein 1
Morbidity
NF-κB
NF-κB protein
obstructive sleep apnea
Patients
Respiration
Sleep apnea
Sleep disorders
Stem cells
Transcription factors
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Summary:Cardiovascular morbidity is the leading cause of death of obstructive sleep apnea (OSA) syndrome patients. Nocturnal airway obstruction is associated with intermittent hypoxia (IH). In our previous work with cell lines, incubation with sera from OSA patients induced changes in cell morphology, NF-κB activation and decreased viability. A decrease in beating rate, contraction amplitude and a reduction in intracellular calcium signaling was also observed in human cardiomyocytes differentiated from human embryonic stem cells (hESC-CMs). We expanded these observations using a new controlled IH in vitro system on beating hESC-CMs. The Oxy-Cycler system was programed to generate IH cycles. Following IH, we detected the activation of Hif-1α as an indicator of hypoxia and nuclear NF-κB p65 and p50 subunits, representing pro-inflammatory activity. We also detected the secretion of inflammatory cytokines, such as MIF, PAI-1, MCP-1 and CXCL1, and demonstrated a decrease in beating rate of hESC-CMs following IH. IH induces the co-activation of inflammatory features together with cardiomyocyte alterations which are consistent with myocardial damage in OSA. This study provides an innovative approach for in vitro studies of OSA cardiovascular morbidity and supports the search for new pharmacological agents and molecular targets to improve diagnosis and treatment of patients.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms231810272