Abstract
Obstructive sleep apnea (OSA) is a chronic condition characterized by recurrent pauses in breathing caused by the collapse of the upper airways, which results in intermittent hypoxia and arousals during the night. The disorder is associated with a vast number of comorbidities affecting different systems, including cardiovascular, metabolic, psychiatric, and neurological complications. Due to abnormal sleep architecture, OSA patients are at high risk of circadian clock disruption, as has been reported in several recent studies. The circadian clock affects almost all daily behavioral patterns, as well as a plethora of physiological processes, and might be one of the key factors contributing to OSA complications. An intricate interaction between the circadian clock and hypoxia may further affect these processes, which has a strong foundation on the molecular level. Recent studies revealed an interaction between hypoxia-inducible factor 1 (HIF-1), a key regulator of oxygen metabolism, and elements of circadian clocks. This relationship has a strong base in the structure of involved elements, as HIF-1 as well as PER, CLOCK, and BMAL, belong to the same Per-Arnt-Sim domain family. Therefore, this review summarizes the available knowledge on the molecular mechanism of circadian clock disruption and its influence on the development and progression of OSA comorbidities.
Highlights
Glutamate acts on Nmethyl-D-aspartate receptors (NMDAR), which leads to signal transmission by increasing intracellular calcium and cyclic adenosine monophosphate synthesis in suprachiasmatic nucleus (SCN)
The mammalian circadian clock is based on a transcriptional negative feedback loop between activators and repressors [10], whose function is regulated by kinases and phosphatases [11]
Peek et al found that BMAL1 expression disruption leads to an increased level of HIF-1α and the overexpression of its metabolic targets: prolyl hydroxylase 3 (PHD3), vascular endothelial growth factor (VEGF), and lactate dehydrogenase A (LDHA)
Summary
The circadian clock is a complex, hierarchical timing system whose molecular elements are located in nearly every body cell. They are under the control of the master circadian pacemaker located in the suprachiasmatic nucleus (SCN) of the hypothalamus [1], which features a very similar molecular machinery to the peripheral circadian clock in the body cells. The master clock generates a pronounced circadian rhythm of neuronal firing frequency, which, through a variety of direct and indirect output pathways, synchronizes other cells throughout the body [2]. Phosphorylates cAMP-responsive element-binding protein (CREB) [7]. CREB is an active transcription factor, which binds to calcium/cAMP regulatory elements (CREs) in promotors of repressors genes, including Per and Per2 [8], and stimulates their transcription. SCN neurons are heterogenic and they differ in their pacemaking ability, neuropeptide expression, and response to environmental timing cues, as well as the rhythms they control [6]
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