scholarly journals Relationship between HIF-1 and Circadian Clock Proteins in Obstructive Sleep Apnea Patients—Preliminary Study

2020 ◽  
Vol 9 (5) ◽  
pp. 1599 ◽  
Author(s):  
Agata Gabryelska ◽  
Marcin Sochal ◽  
Szymon Turkiewicz ◽  
Piotr Białasiewicz
Keyword(s):  
Obstructive Sleep Apnea ◽  
Sleep Apnea ◽  
Circadian Clock ◽  
Protein Level ◽  
Hypoxia Inducible Factor ◽  
Apnea Hypopnea Index ◽  
Clock Proteins ◽  
Obstructive Sleep ◽  
Healthy Control ◽  
Circadian Clock Proteins

Obstructive sleep apnea (OSA) is characterized by intermittent hypoxia and associated with the disruption of circadian rhythm. The study aimed to assess the relationship between hypoxia-inducible factor (HIF) subunits, circadian clock proteins, and polysomnography (PSG) variables, in healthy individuals and severe OSA patients. The study included 20 individuals, who underwent PSG and were divided into severe OSA group (n = 10; AHI ≥ 30) and healthy control (n = 10; AHI < 5) based on apnea-hypopnea index (AHI). All participants had their peripheral blood collected in the evening before and the morning after the PSG. HIF-1α, HIF-1β, BMAL1, CLOCK, CRY1, and PER1 protein concertation measurements were performed using ELISA. In a multivariate general linear model with the concentration of all circadian clock proteins as dependent variables, evening HIF-1α protein level was the only significant covariant (p = 0.025). Corrected models were significant for morning and evening PER1 (p = 0.008 and p = 0.006, respectively), evening (p = 0.043), and evening BMAL protein level (p = 0.046). In corrected models, evening HIF-1α protein level had an influence only on the evening PER1 protein level. Results suggest that OSA patients are at risk for developing circadian clock disruption. This process might be mediated by subunit α of HIF-1, as its increased protein level is associated with overexpression of circadian clock proteins.

scholarly journals 0170 Association of HIF-1 Alpha and Beta Subunits with Clock and BMAL1 Proteins in Obstructive Sleep Apnea Patients

SLEEP ◽  
2020 ◽  
Vol 43 (Supplement_1) ◽  
pp. A67-A67
Author(s):  
A Gabryelska ◽  
M Sochal ◽  
S Turkiewicz ◽  
P Bialasiewicz
Keyword(s):  
Obstructive Sleep Apnea ◽  
Sleep Apnea ◽  
Circadian Clock ◽  
Hypoxia Inducible Factor ◽  
Study Groups ◽  
Oxygen Metabolism ◽  
Apnea Hypopnea Index ◽  
Protein Levels ◽  
Obstructive Sleep ◽  
Significant Difference

Abstract Introduction Obstructive sleep apnea (OSA) is a chronic condition that is characterized by intermittent hypoxia. Key regulator of oxygen metabolism is hypoxia inducible factor (HIF), which consists of oxygen sensitive subunit and continuously produced subunit. Circadian clock is composed of set of genes, which function as activators - CLOCK and BMAL 1, who similarly to HIF are basic helix-loop-helix-PER-ARNT-SIM transcription factors. Therefore, the aim of the study was to assess the relationship between HIF-1alpha, HIF-1beta, CLOCK, BMAL1 and polysomnography (PSG) variables in healthy individuals and severe OSA patients. Methods The study included 20 individuals, who underwent PSG and based on apnea-hypopnea index (AHI) were divided into severe OSA group (n=10; AHI30; 90% male) and healthy control (n=10; AHI&lt;5; 70% male). All participants had their peripheral blood collected in the evening (9:00-10:00 pm) before and in the morning (6:00-7:00 am) after the PSG. HIF-1alpha, HIF-1beta, CLOCK and BMAL1 protein concertation measurements were performed using ELISA. Results Significant difference was observed in the following protein measurements between study groups: evening and morning HIF-1 (p=0.020 and p=0.043, respectively), evening HIF-1alpha (p=0.047), evening and morning CLOCK (p=0.037 and p=0.019, respectively) and morning BMAL1 (p=0.016). No differences were observed between morning and evening protein levels in both groups. Evening HIF-1beta corraleted with evening CLOCK and morning BMAL1 (R=0.511, p=0.21 and R=0.594, p=0.006, respectively), while morning HIF-1 with evening BMAL1 (R=474, p=0.35). Furthermore, evening and morning HIF-1 correlated with evening BMAL1 (R=564, p=0.010 and R=0.689, p=0.001, respectively). Additionally, morning CLOCK and BMAL1 correlated with AHI (R=0.510, p=0.022 and R=0.560, p=0.010, respectively) and desaturation index (R=0.487, p=0.209 and R=0.570, p=0.009, respectively). Conclusion There is significant correlation between both subunits of HIF-1 protein and circadian clock proteins: CLOCK and BMAL1, which further correlate with increased disease severity. This suggests OSA patients are in risk of circadian clock disruption due to present hypoxia. Support The study was financed by Polish National Centre Grant no. 2018/31/N/NZ5/03931.

scholarly journals 0059 Disruption of Circadian Clock Proteins in Obstructive Sleep Apnea Patients

SLEEP ◽  
2020 ◽  
Vol 43 (Supplement_1) ◽  
pp. A23-A24
Author(s):  
A Gabryelska ◽  
M Sochal ◽  
P Bialasiewicz
Keyword(s):  
Obstructive Sleep Apnea ◽  
Sleep Apnea ◽  
Circadian Clock ◽  
Regulatory Elements ◽  
Desaturation Index ◽  
Clock Proteins ◽  
Repressor Proteins ◽  
Obstructive Sleep ◽  
Significant Difference ◽  
Circadian Clock Proteins

Abstract Introduction Circadian clocks are endogenous coordinators of 24-hour rhythm of behavioral and molecular processes in living organism. They are composed of set of genes, which function as activators - CLOCK and BMAL1, which through binding to regulatory elements containing E-boxes activate transcription of repressor proteins Period (PER1) and cryptochrome (CRY1). The aim of the study was to assess: CLOCK, BMAL1, PER1 and CRY1 in obstructive sleep apnea (OSA) patients. Methods The study included 20 individuals, who underwent PSG and based on apnea-hypopnea index (AHI) were divided into severe OSA group (n=10; AHI30; 90% male) and healthy control (n=10; AHI&lt;5; 70% male). All participants had their peripheral blood collected in the evening (9:00-10:00 pm) before and in the morning (6:00-7:00 am) after the PSG. CLOCK, BMAL1, CRY1 and PER1 protein concertation measurements were performed using ELISA. Results Increased level of following proteins was observed in OSA group: evening CLOCK (p=0.037), morning CLOCK (p=0.019), morning BMAL1 (p=0.0.16), evening PER1 (p=0.004), morning PER1 (p=0.029) and evening CRY1 (p=0.035). Yet, no significant difference was found between morning and evening level of any of the proteins in OSA and control group. Additionally, morning level of activator proteins CLOCK and BMAL1 had positive correlation with AHI (p=0.022, R=0.510 and p=0.010, R=0.560, respectively) and desaturation index (p=0.209, R=0.487 and p=0.009, R=0.570, respectively), while for repressor proteins PER1 and CRY1 significant correlations were found with desaturation index in the evening (p=0.025, R=0.500 and p=0.048, R=0.448, respectively), AHI in REM stage (p=0.009, R=0.569 and p=0.027, R=0.495, respectively) and AHI (for PER1 only p=0.014, R=0.540). Conclusion OSA patients have increased level of circadian clock proteins that corelates with severity of the disease. Further research is needed into the disruption of circadian clock should in OSA patients and possible effect of OSA treatment on concentrations of these proteins should be investigated. Support The study was financed by Polish National Centre Grant no. 2018/31/N/NZ5/03931.

scholarly journals Urine 5-Eicosatetraenoic Acids as Diagnostic Markers for Obstructive Sleep Apnea

Antioxidants ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1242
Author(s):  
Hyun-Woo Shin ◽  
Kumsun Cho ◽  
Chae-Seo Rhee ◽  
Il-Hee Hong ◽  
Seok Hyun Cho ◽  
...  
Keyword(s):  
Obstructive Sleep Apnea ◽  
Sleep Apnea ◽  
Intermittent Hypoxia ◽  
Mononuclear Cells ◽  
Hypoxia Inducible Factor ◽  
Apnea Hypopnea Index ◽  
Hypoxia Inducible Factor 1 ◽  
Human Mononuclear Cells ◽  
Obstructive Sleep ◽  
Arachidonic Acid Derivatives

Early detection of obstructive sleep apnea (OSA) is needed to reduce cardiovascular sequelae and mortality. Full-night polysomnography has been used for diagnosing OSA, but it is too expensive and inconvenient for patients to handle. Metabolome-wide analyses were performed to find and validate surrogate markers for OSA. We further investigated the mechanism underlying hypoxic induction of the markers in human cells and mice. Arachidonic acid derivatives 5-HETE and 5-oxoETE were detected in urine samples. The levels (mean ± SD, ng per mg creatinine) of 5-HETE and 5-oxoETE were 56.4 ± 26.2 and 46.9 ± 18.4 in OSA patients, respectively, which were significantly higher than those in controls (22.5 ± 4.6 and 18.7 ± 3.6). Both levels correlated with the apnea-hypopnea index and the lowest oxygen saturation on polysomnography. After the treatment with the continuous positive airway pressure, the metabolite levels were significantly reduced compared with those before the treatment. In human mononuclear cells subjected to intermittent hypoxia, 5-HETE and 5-oxoETE productions were induced by hypoxia-inducible factor 1 and glutathione peroxidase. When mice were exposed to intermittent hypoxia, 5-HETE and 5-oxoETE were excreted more in urine. They were identified and verified as new OSA markers reflecting hypoxic stress. The OSA markers could be used for OSA diagnosis and therapeutic evaluation.

scholarly journals P060 Hypoxia-induced overexpression of Rev-Erb-alpha and NPAS2 proteins in obstructive sleep apnea patients - possible mechanism of DM2 development

2021 ◽  
Vol 2 (Supplement_1) ◽  
pp. A41-A41
Author(s):  
F Karuga ◽  
S Turkiewicz ◽  
M Ditmer ◽  
M Sochal ◽  
P Białasiewicz ◽  
...  
Keyword(s):  
Obstructive Sleep Apnea ◽  
Sleep Apnea ◽  
Serum Protein ◽  
Protein Level ◽  
Control Group ◽  
Apnea Hypopnea Index ◽  
Orphan Nuclear Receptor ◽  
Protein Levels ◽  
Obstructive Sleep ◽  
Significant Difference

Abstract Circadian clocks are endogenous coordinators of 24-hour behavioral and molecular rhythms, which disruption may be caused by obstructive sleep apnea (OSA). It is composed of a set of genes, function as activators (CLOCK, BMAL) or repressors (PER, CRY). Neuronal PAS Domain Protein 2 (NPAS2) can substitute CLOCK in its function. Orphan nuclear receptor (Rev-Erb-α) is another protein supporting the CLOCK-BMAL1 complex, forming the loop which helps to regulate their expression. There are studies suggesting the significant influence of circadian disruption mediated via NPAS2 and Rev-Erb-α on DM2 development. The aim of the study was to determine the role of NPAS2 and Rev-Erb-α in DM2 for OSA patients. All participants underwent polysomnography (PSG) examination. Based on apnea-hypopnea index accompanied by clinical data the recruited individuals (n=40) were assigned to one from 3 groups: OSA (severe OSA, no DM2; n=17), DM2 (severe OSA + DM2; n=7) and control group (no OSA, no DM2; n=16). Serum protein levels of Rev-Erb-α and NPAS2 were assessed with ELISA immunoassay. Analysis between the groups revealed the statistically significant difference only in NPAS2 protein level (p=0.037). Further post-hoc analysis revealed significant differences between OSA and the control group (p=0.017). Moreover, a statistically significant correlation between AHI and NPAS2 serum protein level was observed (r=-0.478, p=0.002). NPAS2 protein levels are associated with a number of apneas and hypopneas during the REM phase of sleep and might have a significant role in the development of OSA complications. However, further studies are needed to understand its role.

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

2022 ◽  
Vol 23 (2) ◽  
pp. 709
Author(s):  
Agata Gabryelska ◽  
Szymon Turkiewicz ◽  
Filip Franciszek Karuga ◽  
Marcin Sochal ◽  
Dominik Strzelecki ◽  
...  
Keyword(s):  
Obstructive Sleep Apnea ◽  
Sleep Apnea ◽  
Circadian Clock ◽  
Hypoxia Inducible Factor ◽  
Oxygen Metabolism ◽  
Neurological Complications ◽  
Upper Airways ◽  
Strong Base ◽  
Vast Number ◽  
Obstructive Sleep

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.

Improvement in Obstructive Sleep Apnea (OSA) in Super Morbidly Obese Patients After Bariatric Surgery

2020 ◽  
Vol 103 (8) ◽  
pp. 725-728
Keyword(s):  
Bariatric Surgery ◽  
Obstructive Sleep Apnea ◽  
Sleep Apnea ◽  
Lifestyle Modification ◽  
Apnea Hypopnea Index ◽  
Morbidly Obese ◽  
Obese Patients ◽  
Obstructive Sleep ◽  
Objective Evidence

Background: Lifestyle modification is the mainstay therapy for obese patients with obstructive sleep apnea (OSA). However, most of these patients are unable to lose the necessary weight, and bariatric surgery (BS) has been proven to be an effective modality in selected cases. Objective: To provide objective evidence that BS can improve OSA severity. Materials and Methods: A prospective study was conducted in super morbidly obese patients (body mass index [BMI] greater than 40 kg/m² or BMI greater than 35 kg/m² with uncontrolled comorbidities) scheduled for BS. Polysomnography (PSG) was performed for preoperative assessment and OSA was treated accordingly. After successful surgery, patients were invited to perform follow-up PSG at 3, 6, and 12 months. Results: Twenty-four patients with a mean age of 35.0±14.0 years were enrolled. After a mean follow-up period of 7.8±3.4 months, the mean BMI, Epworth sleepiness scale (ESS), and apnea-hypopnea index (AHI) significantly decreased from 51.6±8.7 to 38.2±6.8 kg/m² (p<0.001), from 8.7±5.9 to 4.7±3.5 (p=0.003), and from 87.6±38.9 to 28.5±21.5 events/hour (p<0.001), respectively. Conclusion: BS was shown to dramatically improve clinical and sleep parameters in super morbidly obese patients. Keywords: Morbid obesity, Bariatric surgery, Obstructive sleep apnea (OSA)

Aerodynamics Analysis of the Impact of Nasal Surgery on Patients with Obstructive Sleep Apnea and Nasal Obstruction

ORL ◽  
2021 ◽  
pp. 1-8
Author(s):  
Lifeng Li ◽  
Demin Han ◽  
Hongrui Zang ◽  
Nyall R. London
Keyword(s):  
Obstructive Sleep Apnea ◽  
Sleep Apnea ◽  
Nasal Obstruction ◽  
Upper Airway ◽  
Apnea Hypopnea Index ◽  
Nasal Surgery ◽  
Subjective Sleep Quality ◽  
Obstructive Sleep ◽  
Significant Difference ◽  
The Impact

<b><i>Objective:</i></b> The purpose of this study was to evaluate the effects of nasal surgery on airflow characteristics in patients with obstructive sleep apnea (OSA) by comparing the alterations of airflow characteristics within the nasal and palatopharyngeal cavities. <b><i>Methods:</i></b> Thirty patients with OSA and nasal obstruction who underwent nasal surgery were enrolled. A pre- and postoperative 3-dimensional model was constructed, and alterations of airflow characteristics were assessed using the method of computational fluid dynamics. The other subjective and objective clinical indices were also assessed. <b><i>Results:</i></b> By comparison with the preoperative value, all postoperative subjective symptoms statistically improved (<i>p</i> &#x3c; 0.05), while the Apnea-Hypopnea Index (AHI) changed little (<i>p</i> = 0.492); the postoperative airflow velocity and pressure in both nasal and palatopharyngeal cavities, nasal and palatopharyngeal pressure differences, and total upper airway resistance statistically decreased (all <i>p</i> &#x3c; 0.01). A significant difference was derived for correlation between the alteration of simulation metrics with subjective improvements (<i>p</i> &#x3c; 0.05), except with the AHI (<i>p</i> &#x3e; 0.05). <b><i>Conclusion:</i></b> Nasal surgery can decrease the total resistance of the upper airway and increase the nasal airflow volume and subjective sleep quality in patients with OSA and nasal obstruction. The altered airflow characteristics might contribute to the postoperative reduction of pharyngeal collapse in a subset of OSA patients.

scholarly journals High Plasma Cystine Levels Are Associated with Blood Pressure and Reversed by CPAP in Patients with Obstructive Sleep Apnea

2021 ◽  
Vol 10 (7) ◽  
pp. 1387
Author(s):  
Raphael Boneberg ◽  
Anita Pardun ◽  
Lena Hannemann ◽  
Olaf Hildebrandt ◽  
Ulrich Koehler ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Obstructive Sleep Apnea ◽  
Sleep Apnea ◽  
Mononuclear Cells ◽  
Vascular Risk Factor ◽  
High Plasma ◽  
Apnea Hypopnea Index ◽  
Hypoxic Stress ◽  
Peripheral Blood Mononuclear ◽  
Obstructive Sleep

Obstructive sleep apnea (OSA) independent of obesity (OBS) imposes severe cardiovascular risk. To what extent plasma cystine concentration (CySS), a novel pro-oxidative vascular risk factor, is increased in OSA with or without OBS is presently unknown. We therefore studied CySS together with the redox state and precursor amino acids of glutathione (GSH) in peripheral blood mononuclear cells (PBMC) in untreated male patients with OSA (apnea-hypopnea-index (AHI) > 15 h−1, n = 28) compared to healthy male controls (n = 25) stratifying for BMI ≥ or < 30 kg m−2. Fifteen OSA patients were reassessed after 3–5-months CPAP. CySS correlated with cumulative time at an O2-saturation <90% (Tu90%) (r = 0.34, p < 0.05) beside BMI (r = 0.58, p < 0.001) and was higher in subjects with “hypoxic stress” (59.4 ± 2.0 vs. 50.1 ± 2.7 µM, p < 0.01) defined as Tu90% ≥ 15.2 min (corresponding to AHI ≥ 15 h−1). Moreover, CySS significantly correlated with systolic (r = 0.32, p < 0.05) and diastolic (r = 0.31, p < 0.05) blood pressure. CPAP significantly lowered CySS along with blood pressure at unchanged BMI. Unexpectedly, GSH antioxidant capacity in PBMC was increased with OSA and reversed with CPAP. Plasma CySS levels are increased with OSA-related hypoxic stress and associated with higher blood pressure. CPAP decreases both CySS and blood pressure. The role of CySS in OSA-related vascular endpoints and their prevention by CPAP warrants further studies.

scholarly journals Altered K-complex morphology during sustained inspiratory airflow limitation is associated with next-day lapses in vigilance in obstructive sleep apnea

SLEEP ◽  
2021 ◽  
Author(s):  
Ankit Parekh ◽  
Korey Kam ◽  
Anna E Mullins ◽  
Bresne Castillo ◽  
Asem Berkalieva ◽  
...  
Keyword(s):  
Obstructive Sleep Apnea ◽  
Sleep Apnea ◽  
Spectral Characteristics ◽  
Sleep Time ◽  
Airflow Limitation ◽  
Apnea Hypopnea Index ◽  
Complex Morphology ◽  
Obstructive Sleep ◽  
Inspiratory Airflow Limitation ◽  
Psychomotor Vigilance

Abstract Study Objectives Determine if changes in K-complexes associated with sustained inspiratory airflow limitation (SIFL) during N2 sleep are associated with next-day vigilance and objective sleepiness. Methods Data from thirty subjects with moderate-to-severe obstructive sleep apnea who completed three in-lab polysomnograms: diagnostic, on therapeutic continuous positive airway pressure (CPAP), and on suboptimal CPAP (4 cmH2O below optimal titrated CPAP level) were analyzed. Four 20-min psychomotor vigilance tests (PVT) were performed after each PSG, every 2 h. Changes in the proportion of spontaneous K-complexes and spectral characteristics surrounding K-complexes were evaluated for K-complexes associated with both delta (∆SWAK), alpha (∆αK) frequencies. Results Suboptimal CPAP induced SIFL (14.7 (20.9) vs 2.9 (9.2); %total sleep time, p &lt; 0.001) with a small increase in apnea–hypopnea index (AHI3A: 6.5 (7.7) vs 1.9 (2.3); p &lt; 0.01) versus optimal CPAP. K-complex density (num./min of stage N2) was higher on suboptimal CPAP (0.97 ± 0.7 vs 0.65±0.5, #/min, mean ± SD, p &lt; 0.01) above and beyond the effect of age, sex, AHI3A, and duration of SIFL. A decrease in ∆SWAK with suboptimal CPAP was associated with increased PVT lapses and explained 17% of additional variance in PVT lapses. Within-night during suboptimal CPAP K-complexes appeared to alternate between promoting sleep and as arousal surrogates. Electroencephalographic changes were not associated with objective sleepiness. Conclusions Sustained inspiratory airflow limitation is associated with altered K-complex morphology including the increased occurrence of K-complexes with bursts of alpha as arousal surrogates. These findings suggest that sustained inspiratory flow limitation may be associated with nonvisible sleep fragmentation and contribute to increased lapses in vigilance.

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