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

Abstract

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.

High serum Bhlhe40 levels are associated with subclinical atherosclerosis in patients with type 2 diabetes mellitus: A cross-sectional study

“…9 At the population level, the expression of Bhlhe40 was positively correlated with IL-6 and total oxidant status levels and negatively related to total antioxidant status levels. 10 In vitro observation showed an elevated proliferation and a declined apoptosis of pulmonary arterial endothelial cells under hypoxia conditions by the upregulation of Bhlhe40. 12 Conversely, our previous studies found a low expression in high glucose-treated VSMCs.…”

“…9 A recent study demonstrated that the high expression of Bhlhe40 was relevant to IR in patients with obstructive sleep apnea and can be utilized for predicting the presence of metabolic syndrome in obstructive sleep apnea individuals. 10 Moreover, chronic inflammation and oxidative stress are two major hallmarks of atherosclerosis. 11 At the cellular level, overexpression of Bhlhe40 upregulated the generation of reactive oxygen species and the expression of pro-inflammatory cytokines, such as interleukin 6 (IL-6), IL-1β, tumour necrosis factor alpha, and monocyte chemoattractant protein-1 in pulmonary arterial smooth muscle cells.…”

Is obstructive sleep apnea a circadian rhythm disorder?

“…DEC1 expression was a predictor of metabolic syndrome in OSA patients and was associated with increased levels of IL‐6. Therefore, the authors postulated DEC1 as a biomarker of OSA‐associated metabolic syndrome (X. Li et al, 2022). However, as circadian gene expression was only evaluated at a single time‐point (morning fasting blood sample), the study did not evaluate circadian oscillation patterns.…”

“…In this model, the circadian system exerts an influence on respiratory events in obstructive sleep apnea (Butler et al, 2015), while OSA dysregulates the circadian system mainly through sleep fragmentation and intermittent hypoxia (HIF‐1 signalling) (Gabryelska, Sochal, et al, 2020; Manella et al, 2020; Noda et al, 2000). Dysregulation of circadian rhythms contributes to alterations in various homeostatic processes, which are involved in the development of OSA‐related comorbidities, such as metabolic syndrome (X. Li et al, 2022), cardiovascular disease (Noda et al, 1998), and cancer (Hunyor & Cook, 2018). With further research, the endogenous circadian system might prove a potential target for OSA treatment, especially for severe OSA and OSA‐related comorbidities that show poor response to CPAP (Moreira et al, 2017).…”

“…Recent research implies the role of circadian rhythm dysregulation in the development and progression of OSA‐related comorbidities (Burioka et al, 2008; Gabryelska, Sochal, et al, 2020; Gaspar et al, 2021; X. Li et al, 2022; Moreira et al, 2017; Xie et al, 2022; Yang et al, 2019). Circadian rhythms are endogenous rhythms with a 24 h periodicity that temporally optimise behaviour and physiology (Patke et al, 2020).…”