Abstract
Obstructive sleep apnea syndrome (OSAS) patients suffer from cardiovascular morbidity, which is the leading cause of death in this disease. Based on our previous work with transformed cell lines and primary rat cardiomyocytes, we determined that upon incubation with sera from pediatric OSAS patients, the cell’s morphology changes, NF-κB pathway is activated, and their beating rate and viability decreases. These results suggest an important link between OSAS, systemic inflammatory signals and end-organ cardiovascular diseases. In this work, we confirmed and expanded these observations on a new in vitro system of beating human cardiomyocytes (CM) differentiated from human embryonic stem cells (hES). Our results show that incubation with pediatric OSAS sera, in contrast to sera from healthy children, induces over-expression of NF-κB p50 and p65 subunits, marked reduction in CMs beating rate, contraction amplitude and a strong reduction in intracellular calcium signal. The use of human CM cells derived from embryonic stem cells has not been previously reported in OSAS research. The results further support the hypothesis that NF-κB dependent inflammatory pathways play an important role in the evolution of cardiovascular morbidity in OSAS. This study uncovers a new model to investigate molecular and functional aspects of cardiovascular pathology in OSAS.
Highlights
Obstructive sleep apnea syndrome (OSAS) is a sleep disorder characterized by repetitive nocturnal upper airway obstructive events, associated with intermittent hypoxia [1]. OSAS is a frequent disorder in children with a prevalence of 1–5%, pediatricOSAS is under-diagnosed because parents under-report its nocturnal symptoms, and upper airway dysfunction is not always apparent to clinicians [2,3]. 4.0/).Untreated pediatric OSAS can be associated with significant neurobehavioral, cognitive, somatic growth, metabolic, and cardiovascular morbidity, the last considered the leading cause of death in this syndrome in adults [4]
Since all the experiments are based on the comparison between control sera and sera from OSAS children, we first determined the minimal concentration of sera which shows an effect but is not toxic to the human embryonic stem cells (hES)-derived CM cell line
The results show that neither control nor OSAS sera are toxic at a 5%
Summary
Obstructive sleep apnea syndrome (OSAS) is a sleep disorder characterized by repetitive nocturnal upper airway obstructive events, associated with intermittent hypoxia [1]. Cardiovascular consequences of OSAS includes: dysregulation of blood pressure (BP), cardiac remodeling, and endothelial dysfunction. The most severe pediatric cardiovascular consequence of OSAS is pulmonary hypertension, and Rt, heart failure (Cor pulmonale), if OSAS is untreated All those conditions are partially reversible with OSAS treatments [5]. Based on our previous studies on a variety of cell types, including newborn rat cardiomyocytes [11,13], where NF-κB was shown to be activated by sera from OSAS children, we hypothesized that the activation of the NF-κB pathway is involved in the pathophysiology of OSAS-related cardiac morbidity. By studying human beating CMs, we have improved our ability to assess by several techniques, the behavior of cells once exposed to disease mimicking conditions such as incubation with sera from OSAS patients. By better defining and understanding the complex array of molecular, cellular, and physiological factors involved in OSAS, it will be possible to develop short- and long-term controlled anti-inflammatory agents to prevent or ameliorate cardiac morbidity
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