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

Abstract

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.

Is obstructive sleep apnea a circadian rhythm disorder?

“…In this study, however, clock gene expression was not significantly altered in OSA patients, while the morning–evening variation of BMAL1 and RORA expression was increased in participants with nocturnal hypoxaemia. CRY2 and TIMELESS mRNA levels decreased with increasing AHI, and a positive correlation was noted between HIF1A and CRY1 expression (Xie et al, 2022), which reflected the findings of Gabryelska et al, in which the evening levels of CRY1 protein positively correlated with HIF‐1α protein levels (Gabryelska, Sochal, et al, 2020). Further research on larger cohorts is necessary to evaluate the relationship between OSA, HIF1A and clock gene expression at multiple time points during the day and over longer time periods.…”

“…Furthermore, the use of different markers to evaluate circadian characteristics, such as plasma or salivary melatonin levels (Gaspar et al, 2021; Hernández et al, 2007; Papaioannou et al, 2012), expression of a different number of various circadian genes in PBMCs (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), heart rate variability (Noda et al, 1998), actimetry parameters (Butler et al, 2015), and alterations in hormone levels or inflammatory molecules (Burioka et al, 2008), encumbers the comparison between studies. In regard to sample structure and the small number of control subjects in the majority of studies, it is worth noting that including healthy subjects in sleep studies is challenging due to the limited availability of polysomnography.…”

“…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).…”

“…Although the exact mechanisms remain to be elucidated, the interaction between obstructive sleep apnea and circadian dysregulation appears to be bidirectional. The circadian system influences the pattern of respiratory events in OSA (Butler et al, 2015), which may promote circadian dysregulation through hypoxia signalling and sleep fragmentation (Gabryelska, Sochal, et al, 2020; Manella et al, 2020; Noda et al, 2000; Xie et al, 2022). Although obstructive sleep apnea is currently not classified as a circadian rhythm sleep disorder (CRSD), both pathogenetic entities share common symptoms and comorbidities (Zee et al, 2013).…”

Research progress of drosophila biological clock genes involved in sleep regulation

“…The patients with OSA expressd more morning-evening variation(MEV) for HIF1α mRNA than the age-matched control patients without OSA( significantly by 23%, P=0.008). The gene expression levels decreased with the apnea hypopnea index(AHI) [24]. Some scholars included 133 OSA patients and 11 controls without OSA to observe the regulation and expression of core clock genes.…”