Assessment of continuous positive airway pressure effect on the circadian clock signaling pathway in obstructive sleep apnea patients

Circadian clock disruption, represented by alteration of the particular set of genes – CLOCK, CRY1, BMAL1, PER1 – can be one of the OSA consequences, leading to further health complications. CPAP treatment as the gold standard for OSA has been associated with the improvement of life quality, e.g. reducing the risk of premature death, metabolic and cardiovascular comorbidities, or cognitive impairment – major circadian clock disruption outcomes25. Our study demonstrated that one-night CPAP treatment has an impact on the circadian clock gene expression in moderate-to-severe OSA patients.

In our recent study, we found that OSA patients were characterized by elevated protein concentrations of CLOCK, PER1, and CRY1 in the evening and CLOCK, BMAL1, and PER1 in the morning, before and after PSG8. In this study, first, we assessed changes in concentrations of circadian clock proteins during PSG at both time points, which did not reveal any statistically significant. It would correctly expect a constant concentration of CLOCK and BMAL1 proteins, both in the morning and in the evening. In turn, repressors (PER1 and CRY1) should show circadian variability. Their concentrations should be highest in the evening and lowest in the morning. However, we observed an increase in CLOCK and CRY1 gene expression in the morning after PSG, which is supported by results by Moreira et al. noted that the CLOCK gene is over-expressed in the OSA population20. BMAL1-CLOCK is an active transcription complex that leads to increased expression of repressors. Next, CRY and PER are trans located to the cytoplasm, where they are phosphorylated and make hetero-dimer, which inhibits activators in the nucleus26. At the same time, there is continuous ubiquitin-dependent degradation of repressors26. Repressor protein concentrations peak in the evening, which leads to stopping their expression, and further to the lowest levels in the morning8,26. Those oscillations may be altered in OSA patients, due to the increased activity of hypoxia-inducible factor 1 (HIF-1), which is a complex of helix-loop-helix (bHLH)—Per/Arnt/Sim (PAS) transcription factor family proteins27. Among its targets are circadian clock repressor genes, which have hypoxia response elements in their gene promotors. Thus, the hypoxia state in OSA can increase the expression of PER1 and CRY1 and might disable the negative feedback loop, which may diminish the differences between evening and morning repressor (PER1 and CRY1) levels and might explain the lack of protein concentration differences. It would be confirmed by increased protein levels and expression of PER1 in the morning after PSG in comparison to the evening before PSG, which was shown in our study. However, those differences were not statistically significant.

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