Abstract
Obstructive sleep apnea syndrome (OSA) is associated with cardiovascular morbidity in adults and children. NFκB activity is enhanced in circulating monocytes of adults with OSA, that decreases following positive pressure therapy. OSA children’s serum activates NFκB in a cell line. We hypothesized that OSA children’s serum can activate NFκB in cardiomyocytes (CM) and effect their viability. In order to explore the role played by NFκB in OSA cardiovascular pathophysiology, rat, mouse and human immortalized CM were exposed to human serum drawn from OSA children and matched controls. Increased expression of NFκB classical subunits p65/p50 as well as major morphological changes occurred in cardiomyocytes following OSA’s serum exposure. OSA children’s serum induced NFκB activity as measured by p65 nuclear translocation in immortalized human CM and rat cardiomyocytes as well as dense immunostaining of the nucleus. Trypan blue and XTT assays showed that OSA sera induced CM apoptosis. We conclude that NFκB is systemically activated in cardiomyocytes, who also demonstrate decreased viability and contractility following exposure to OSA serum. It supports the hypothesis NFκB plays a role in the evolution of cardiovascular morbidity in OSA. It may support the search for new therapeutic interventions controlling NFκB activation in OSA.
Highlights
Obstructive sleep apnea syndrome (OSA) is associated with cardiovascular morbidity in adults and children
Children with moderate to severe OSA, as defined by polysomnography are usually treated with Adenotonsillectomy (T&A)[4,5]
nuclear factor κB (NF-κB) activity is increased in circulating neutrophils and monocytes, and decreases following conventional l therapy with continuous positive airway pressure (CPAP)[8,9]
Summary
We exposed rat CM to OSA and non-OSA sera different samples. Active NFκB sub-units are disassociated from IκB and may enter the nucleus, where they bind to specific recognition sites in the DNA We assessed this activation by tracking the translocation of the subunits into the nucleus with two methods: western blot in nuclear lysates (Fig. 2), and immunohistochemistry of P50 and P65 (Fig. 3). Immunostaining for NFκB subunits P50 and P65 in neonatal rat CM treated for 48 h showed increased dense staining in the cells’ nuclei in CM treated by OSA sera in comparison to those treated by non-OSA serum. We detected increased phosphorylation ratio levels of IKK in nuclear lysates prepared by a specific protocol from neonatal rat CM exposed to OSA compared to non-OSA sera (Fig. 4). Trypan blue and XTT assay kit were used for this purpose (Fig. 7)
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