Disruption of Circadian Rhythm Genes in Obstructive Sleep Apnea Patients—Possible Mechanisms Involved and Clinical Implication

Gabryelska, Agata; Turkiewicz, Szymon; Karuga, Filip Franciszek; Sochal, Marcin; Strzelecki, Dominik; Białasiewicz, Piotr

doi:10.3390/ijms23020709

Cited by 21 publications

(10 citation statements)

References 133 publications

(164 reference statements)

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“… 11 It is speculated that the disrupted expression of circadian genes induced by OSA through the hypoxia-inducible factor (HIF) pathway could result in an increased risk of a variety of metabolic diseases and cardiovascular diseases. 12 Investigating the association between HIF and the expression of circadian genes could enhance our understanding of the pathophysiology of OSA and help reduce complications associated with this condition.…”

Section: Introductionmentioning

confidence: 99%

The Relationship Between HIF1α and Clock Gene Expression in Patients with Obstructive Sleep Apnea

Xie

Guo

Luo

et al. 2022

NSS

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Purpose In this study, we aimed to investigate the precise relationship between hypoxia-inducible factor 1α (HIF1α), circadian clock genes, and OSA. Methods We recruited 21 patients with OSA and 22 age-matched controls who underwent polysomnography and had their peripheral blood collected on the evening before and the morning after sleep. OSA was defined as an apnea hypopnea index (AHI) ≥15 events/h. Patients in which T90 > 0 were defined as having nocturnal hypoxemia (NH) and were referred to as the NH group. The mRNA levels of HIF1α, HIF1β and several clock genes ( Timeles s, Clock, Bmal1, Per1, Per2, Per3, Cry1, Cry2, Ck1δ, Rorα, NR1D1 , and NPAS2) were determined by RT-qPCR. The percentage difference in gene expression levels when compared between the morning and evening was then determined as referred to as morning-evening variation (MEV). Results The MEV for HIF1α mRNA expression in OSA patients increased significantly by 23% ( P = 0.008) when compared to patients without OSA. The gene expression levels of Timeless ( P = 0.038) and Cry2 ( P = 0.012) decreased with AHI. The MEV of Bmal1, Rorα , and HIF1α mRNA levels were upregulated by 16% ( P = 0.006), 14% ( P = 0.027), and 25% ( P = 0.005), respectively, in participants with NH when compared to those without NH. Furthermore, the MEV for HIF1α mRNA levels was positively correlated with the MEV of Bmal1, Cry1 , and CK1δ mRNA levels ( R = 0.638, P < 0.001; R = 0.327, P = 0.002; R = 0.332, P = 0.001, respectively) and negatively correlated with LSpO 2 ( R = −0.464, P =0.009) and Mean SpO 2 ( R = −0.500, P = 0.003). Conclusion Our data suggest that patients with OSA or NH tend to develop circadian rhythm disorders that may be induced by the hypoxia-mediated augmentation of HIF1α gene expression in OSA.

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Section: Introductionmentioning

confidence: 99%

The Relationship Between HIF1α and Clock Gene Expression in Patients with Obstructive Sleep Apnea

Xie

Guo

Luo

et al. 2022

NSS

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“…A stable dimeric complex of HIF interacts with gene promoters during hypoxemic conditions. It activates the expression of many genes responsible for, e.g., regulation of glucose metabolism [ 99 ], vessel growth, and the circadian clock [ 17 , 100 , 101 ]. In recent years, several papers have shown increased HIF-1α protein levels in OSA patients [ 102 ].…”

Section: Osa Pain and Hypoxia Markersmentioning

confidence: 99%

The Role of Inflammation, Hypoxia, and Opioid Receptor Expression in Pain Modulation in Patients Suffering from Obstructive Sleep Apnea

Kaczmarski

Karuga

Szmyd

et al. 2022

IJMS

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Obstructive sleep apnea (OSA) is a relatively common disease in the general population. Besides its interaction with many comorbidities, it can also interact with potentially painful conditions and modulate its course. The association between OSA and pain modulation has recently been a topic of concern for many scientists. The mechanism underlying OSA-related pain connection has been linked with different pathophysiological changes in OSA and various pain mechanisms. Furthermore, it may cause both chronic and acute pain aggravation as well as potentially influencing the antinociceptive mechanism. Characteristic changes in OSA such as nocturnal hypoxemia, sleep fragmentation, and systemic inflammation are considered to have a curtailing impact on pain perception. Hypoxemia in OSA has been proven to have a significant impact on increased expression of proinflammatory cytokines influencing the hyperalgesic priming of nociceptors. Moreover, hypoxia markers by themselves are hypothesized to modulate intracellular signal transduction in neurons and have an impact on nociceptive sensitization. Pain management in patients with OSA may create problems arousing from alterations in neuropeptide systems and overexpression of opioid receptors in hypoxia conditions, leading to intensification of side effects, e.g., respiratory depression and increased opioid sensitivity for analgesic effects. In this paper, we summarize the current knowledge regarding pain and pain treatment in OSA with a focus on molecular mechanisms leading to nociceptive modulation.

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“…Both OSA and MetS are closely associated with oxidative stress and systemic inflammation, which were critical physiological rhythms regulated by the clock genes ( Gabryelska et al, 2022 ). As an independent risk factor for MetS, OSA patients are often in a state of IR and endothelial dysfunction ( Stenvers et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Circadian clock disruptions link oxidative stress and systemic inflammation to metabolic syndrome in obstructive sleep apnea patients

Liu

Meng

et al. 2022

Front. Physiol.

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Objectives: Obstructive sleep apnea (OSA) is an independent risk factor for metabolic syndrome (MetS). Recent studies have indicated that circadian clock genes were dysregulated in OSA. In addition, it is clear that the impairment of circadian clocks drives the progression of MetS. Therefore, we hypothesized that circadian rhythm disruption links OSA with MetS.Methods: A total of 118 participants, who underwent polysomnography (PSG) and were diagnosed as healthy snorers (control, n = 29) or OSA (n = 89) patients based on the apnea–hypopnea index (AHI), were enrolled in the present study. General information, anthropometric data, blood biochemical indicators, clock gene expressions, and levels of oxidative and inflammatory indicators were collected, determined, and compared in all the participants.Results: We found that Brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein 1 (Bmal1) and Differentiated embryo chondrocyte 1 (Dec1) were upregulated, while Period 1 (Per1) was reduced in OSA patients. In addition, these changing trends were closely associated with the hypoxia indicator of AHI and have a significant impact on the presence of MetS components, such as hyperglycemia (Dec1 and Per1, p < 0.05 and 0.001, respectively), hypertension (Bmal1 and Dec1, p < 0.001 and 0.01, respectively), hyperlipidemia (Dec1, p < 0.01), and obesity (Dec1, p < 0.05). Notably, expressions of Dec1 correlated with IR and predicted the presence of MetS in OSA patients. Finally, we also observed that Dec1 expression was interrelated with levels of both oxidative indicators and inflammatory biomarkers (IL-6) in OSA.Conclusion: This study concluded that circadian clock disruptions, especially Dec1, link OSA with MetS in an oxidative and inflammatory-related manner. Circadian clock Dec1 can be used as a specific biomarker (p < 0.001) and therapeutic target in OSA combined with Mets patients.

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Disruption of Circadian Rhythm Genes in Obstructive Sleep Apnea Patients—Possible Mechanisms Involved and Clinical Implication

Cited by 21 publications

References 133 publications

The Relationship Between HIF1α and Clock Gene Expression in Patients with Obstructive Sleep Apnea

The Relationship Between HIF1α and Clock Gene Expression in Patients with Obstructive Sleep Apnea

The Role of Inflammation, Hypoxia, and Opioid Receptor Expression in Pain Modulation in Patients Suffering from Obstructive Sleep Apnea

Circadian clock disruptions link oxidative stress and systemic inflammation to metabolic syndrome in obstructive sleep apnea patients

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