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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (15 March 2023) | Viewed by 14517

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Prof. Dr. Shin Takasawa

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Guest Editor

Department of Biochemistry, Nara Medical University (NMU), 840 Shijo-cho, Kashihara 634-8521, Nara, Japan
Interests: diabetes and its complication; sleep apnea; cancer cell biology; CD38-cyclic ADP-ribose signal system; insulin secretion; regeneration biology; regenerating gene (Reg) family
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Special Issue Information

Dear Colleagues,

This Special Issue is the continuation of our previous Special Issues “Sleep Apnea and Intermittent Hypoxia” and “Sleep Apnea and Intermittent Hypoxia 2.0”.

Sleep apnea syndrome (SAS) is a clinical syndrome characterized by repeated episodes of pharyngeal obstruction during sleep that leads to intermittent hypoxia (IH), sleep fragmentation, and excessive daytime sleepiness. It is a highly prevalent disorder, affecting about 14% of men and 5% of women, and its prevalence is rapidly rising because of its strong association with obesity. The major health burden in SAS patients is an increased risk of cardiovascular diseases, such as systemic arterial hypertension, coronary artery disease, heart failure, and stroke, which is an association that is corroborated by numerous large-scale epidemiological and prospective studies. Furthermore, there is increasing evidence of an independent association of SAS with metabolic dysfunction, and, in particular, with alterations in glucose metabolism. Subjects with SAS seem to be at greater risk of developing type 2 diabetes mellitus, insulin resistance, and metabolic syndrome, an association that seems to be, at least in part, irrespective of the degree of obesity. Indeed, SAS and obesity may exert synergistic negative effects on glucose metabolism. However, there are few molecular studies about SAS/IH. This Special Issue aims to provide new findings regarding the molecular events in SAS/IH, as well as their mechanisms.

Prof. Dr. Shin Takasawa
Guest Editor

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Keywords

sleep apnea syndrome
intermittent hypoxia
oxidative stress
gene expression
diabetes
appetite
obesity
hypertension

Published Papers (7 papers)

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Research

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13 pages, 1968 KiB

Open AccessArticle

Sensorimotor Cortical Activity during Respiratory Arousals in Obstructive Sleep Apnea

by Katharina Bahr-Hamm, Nabin Koirala, Marsha Hanif, Haralampos Gouveris and Muthuraman Muthuraman

Int. J. Mol. Sci. 2023, 24(1), 47; https://doi.org/10.3390/ijms24010047 - 20 Dec 2022

Cited by 1 | Viewed by 1591

Abstract

Intensity of respiratory cortical arousals (RCA) is a pathophysiologic trait in obstructive sleep apnea (OSA) patients. We investigated the brain oscillatory features related to respiratory arousals in moderate and severe OSA. Raw electroencephalography (EEG) data recorded during polysomnography (PSG) of 102 OSA patients (32 females, mean age 51.6 ± 12 years) were retrospectively analyzed. Among all patients, 47 had moderate (respiratory distress index, RDI = 15–30/h) and 55 had severe (RDI > 30/h) OSA. Twenty RCA per sleep stage in each patient were randomly selected and a total of 10131 RCAs were analyzed. EEG signals obtained during, five seconds before and after the occurrence of each arousal were analyzed. The entropy (approximate (ApEn) and spectral (SpEn)) during each sleep stage (N1, N2 and REM) and area under the curve (AUC) of the EEG signal during the RCA was computed. Severe OSA compared to moderate OSA patients showed a significant decrease (p < 0.0001) in the AUC of the EEG signal during the RCA. Similarly, a significant decrease in spectral entropy, both before and after the RCA was observed, was observed in severe OSA patients when compared to moderate OSA patients. Contrarily, the approximate entropy showed an inverse pattern. The highest increase in approximate entropy was found in sleep stage N1. In conclusion, the dynamic range of sensorimotor cortical activity during respiratory arousals is sleep-stage specific, dependent on the frequency of respiratory events and uncoupled from autonomic activation. These findings could be useful for differential diagnosis of severe OSA from moderate OSA. Full article

(This article belongs to the Special Issue Sleep Apnea and Intermittent Hypoxia 3.0)

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8 pages, 447 KiB

Open AccessCommunication

Evaluation of HIF-1 Involvement in the BDNF and ProBDNF Signaling Pathways among Obstructive Sleep Apnea Patients

by Agata Gabryelska and Marcin Sochal

Int. J. Mol. Sci. 2022, 23(23), 14876; https://doi.org/10.3390/ijms232314876 - 28 Nov 2022

Cited by 10 | Viewed by 1601

Abstract

Obstructive Sleep Apnea (OSA) is a chronic condition characterized by intermittent hypoxia associated with multiple comorbidities, including psychiatric disorders, such as depression, insomnia, and cognitive impairment. The brain-derived neurotrophic factor (BDNF) and proBDNF singling pathways have been shown to be involved in this group of diseases. Furthermore, their expression might be affected by hypoxia-inducible factor 1 (HIF-1), which is an oxygen sensitive transcription factor due to its alpha subunit. Therefore, this study aimed to evaluate the association between HIF-1

α

, BDNF, and proBDNF protein levels among OSA patients. This study included 40 individuals who underwent polysomnography (PSG) and were divided into the OSA group (n = 20; AHI ≥ 30) and healthy control (n = 20; AHI < 5) based on the apnea–hypopnea index (AHI). All participants had their peripheral blood collected in the evening before and the morning after the PSG. BDNF, proBDNF, and HIF-1α protein concertation measurements were performed using ELISA. No differences were found in BDNF, proBDNF, and HIF-1α protein levels between OSA and the control group, both in the evening and in the morning. In the OSA group, i.e., the linear regression model, the morning BDNF protein level was predicted by age (ß = −0.389, p = 0.023) and the mean SpO2 of desaturations during sleep (ß = −0.577, p = 0.002). This model accounted for 63.3% of the variability in the morning BDNF protein level (F = 14.639, p < 0.001). The morning proBDNF protein level was predicted by age (ß = −0.395, p = 0.033) and HIF-1α morning protein level (ß = −3.192, p = 0.005). This model accounted for 52.4% of the variability in the morning BDNF protein level (F = 9.355, p = 0.002). The obtained results suggest that the HIF-1 transcription factor might be involved in the pathway activated by proBDNF, which may have protective properties from hypoxia in OSA patients. Full article

(This article belongs to the Special Issue Sleep Apnea and Intermittent Hypoxia 3.0)

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19 pages, 3540 KiB

Open AccessArticle

Upregulation of Reg IV and Hgf mRNAs by Intermittent Hypoxia via Downregulation of microRNA-499 in Cardiomyocytes

by Shin Takasawa, Asako Itaya-Hironaka, Mai Makino, Akiyo Yamauchi, Sumiyo Sakuramoto-Tsuchida, Tomoko Uchiyama, Ryogo Shobatake, Yoshinori Takeda and Hiroyo Ota

Int. J. Mol. Sci. 2022, 23(20), 12414; https://doi.org/10.3390/ijms232012414 - 17 Oct 2022

Cited by 2 | Viewed by 1563

Abstract

Sleep apnea syndrome (SAS) is characterized by recurrent episodes of oxygen desaturation and reoxygenation (intermittent hypoxia [IH]), and is a risk factor for cardiovascular disease (CVD) and insulin resistance/Type 2 diabetes. However, the mechanisms linking IH stress and CVD remain elusive. We exposed rat H9c2 and mouse P19.CL6 cardiomyocytes to experimental IH or normoxia for 24 h to analyze the mRNA expression of several cardiomyokines. We found that the mRNA levels of regenerating gene IV (Reg IV) and hepatocyte growth factor (Hgf) in H9c2 and P19.CL6 cardiomyocytes were significantly increased by IH, whereas the promoter activities of the genes were not increased. A target mRNA search of microRNA (miR)s revealed that rat and mouse mRNAs have a potential target sequence for miR-499. The miR-499 level of IH-treated cells was significantly decreased compared to normoxia-treated cells. MiR-499 mimic and non-specific control RNA (miR-499 mimic NC) were introduced into P19.CL6 cells, and the IH-induced upregulation of the genes was abolished by introduction of the miR-499 mimic, but not by the miR-499 mimic NC. These results indicate that IH stress downregulates the miR-499 in cardiomyocytes, resulting in increased levels of Reg IV and Hgf mRNAs, leading to the protection of cardiomyocytes in SAS patients. Full article

(This article belongs to the Special Issue Sleep Apnea and Intermittent Hypoxia 3.0)

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14 pages, 2780 KiB

Open AccessArticle

Downregulation of the Cd38-Cyclic ADP-Ribose Signaling in Cardiomyocytes by Intermittent Hypoxia via Pten Upregulation

by Shin Takasawa, Mai Makino, Tomoko Uchiyama, Akiyo Yamauchi, Sumiyo Sakuramoto-Tsuchida, Asako Itaya-Hironaka, Yoshinori Takeda, Keito Asai, Ryogo Shobatake and Hiroyo Ota

Int. J. Mol. Sci. 2022, 23(15), 8782; https://doi.org/10.3390/ijms23158782 - 7 Aug 2022

Cited by 5 | Viewed by 1960

Abstract

Sleep apnea syndrome (SAS) is characterized by recurrent episodes of oxygen desaturation and reoxygenation (intermittent hypoxia, IH), and it is a risk factor for cardiovascular disease (CVD) and insulin resistance/type 2 diabetes. However, the mechanisms linking IH stress and CVD remain elusive. We exposed rat H9c2 and mouse P19.CL6 cardiomyocytes to experimental IH or normoxia for 24 h to analyze the mRNA expression of the components of Cd38-cyclic ADP-ribose (cADPR) signaling. We found that the mRNA levels of cluster of differentiation 38 (Cd38), type 2 ryanodine receptor (Ryr2), and FK506-binding protein 12.6 (Fkbp12.6) in H9c2 and P19.CL6 cardiomyocytes were significantly decreased by IH, whereas the promoter activities of these genes were not decreased. By contrast, the expression of phosphatase and tensin homolog deleted from chromosome 10 (Pten) was upregulated in IH-treated cells. The small interfering RNA for Pten (siPten) and a non-specific control RNA were introduced into the H9c2 cells. The IH-induced downregulation of Cd38, Ryr2, and Fkbp12.6 was abolished by the introduction of the siPten, but not by the control RNA. These results indicate that IH stress upregulated the Pten in cardiomyocytes, resulting in the decreased mRNA levels of Cd38, Ryr2, and Fkbp12.6, leading to the inhibition of cardiomyocyte functions in SAS patients. Full article

(This article belongs to the Special Issue Sleep Apnea and Intermittent Hypoxia 3.0)

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13 pages, 2527 KiB

Open AccessArticle

Intermittent Hypoxia Increased the Expression of DBH and PNMT in Neuroblastoma Cells via MicroRNA-375-Mediated Mechanism

by Shin Takasawa, Ryogo Shobatake, Yoshinori Takeda, Tomoko Uchiyama, Akiyo Yamauchi, Mai Makino, Sumiyo Sakuramoto-Tsuchida, Keito Asai, Hiroyo Ota and Asako Itaya-Hironaka

Int. J. Mol. Sci. 2022, 23(11), 5868; https://doi.org/10.3390/ijms23115868 - 24 May 2022

Cited by 7 | Viewed by 1967

Abstract

Sleep apnea syndrome (SAS), characterized by recurrent episodes of oxygen desaturation and reoxygenation (intermittent hypoxia (IH)), is a risk factor for hypertension and insulin resistance. We report a correlation between IH and insulin resistance/diabetes. However, the reason why hypertension is induced by IH is elusive. Here, we investigated the effect of IH on the expression of catecholamine-metabolizing enzymes using an in vitro IH system. Human and mouse neuroblastoma cells (NB-1 and Neuro-2a) were exposed to IH or normoxia for 24 h. Real-time RT-PCR revealed that IH significantly increased the mRNA levels of dopamine β-hydroxylase (DBH) and phenylethanolamine N-methyltransferase (PNMT) in both NB-1 and Neuro-2a. Western blot showed that the expression of DBH and PNMT in the NB-1 cells was significantly increased by IH. Reporter assays revealed that promoter activities of DBH and PNMT were not increased by IH. The miR-375 level of IH-treated cells was significantly decreased relative to that of normoxia-treated cells. The IH-induced up-regulation of DBH and PNMT was abolished by the introduction of the miR-375 mimic, but not by the control RNA. These results indicate that IH stress increases levels of DBH and PNMT via the inhibition of miR-375-mediated mRNA degradation, potentially playing a role in the emergence of hypertension in SAS patients. Full article

(This article belongs to the Special Issue Sleep Apnea and Intermittent Hypoxia 3.0)

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Review

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20 pages, 1276 KiB

Open AccessReview

The Impact of Intermittent Hypoxia on Metabolism and Cognition

by Ryogo Shobatake, Hiroyo Ota, Nobuyuki Takahashi, Satoshi Ueno, Kazuma Sugie and Shin Takasawa

Int. J. Mol. Sci. 2022, 23(21), 12957; https://doi.org/10.3390/ijms232112957 - 26 Oct 2022

Cited by 8 | Viewed by 3041

Abstract

Intermittent hypoxia (IH), one of the primary pathologies of sleep apnea syndrome (SAS), exposes cells throughout the body to repeated cycles of hypoxia/normoxia that result in oxidative stress and systemic inflammation. Since SAS is epidemiologically strongly correlated with type 2 diabetes/insulin resistance, obesity, hypertension, and dyslipidemia included in metabolic syndrome, the effects of IH on gene expression in the corresponding cells of each organ have been studied intensively to clarify the molecular mechanism of the association between SAS and metabolic syndrome. Dementia has recently been recognized as a serious health problem due to its increasing incidence, and a large body of evidence has shown its strong correlation with SAS and metabolic disorders. In this narrative review, we first outline the effects of IH on the expression of genes related to metabolism in neuronal cells, pancreatic β cells, hepatocytes, adipocytes, myocytes, and renal cells (mainly based on the results of our experiments). Next, we discuss the literature regarding the mechanisms by which metabolic disorders and IH develop dementia to understand how IH directly and indirectly leads to the development of dementia. Full article

(This article belongs to the Special Issue Sleep Apnea and Intermittent Hypoxia 3.0)

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16 pages, 344 KiB

Open AccessReview

A Narrative Review of the Association between Obstructive Sleep Apnea and Glaucoma in Adults

by Barbara Leggewie, Haralampos Gouveris and Katharina Bahr

Int. J. Mol. Sci. 2022, 23(17), 10080; https://doi.org/10.3390/ijms231710080 - 3 Sep 2022

Cited by 7 | Viewed by 2023

Abstract

Background: Obstructive sleep apnea (OSA) is a sleep disorder, primarily of the upper airway, which not only has a significant impact on quality of life but is also associated with various systemic diseases. Several ophthalmological diseases are also associated with OSA, especially glaucoma. The purpose of this review is to take a closer look at the causality and mutual influence. Methods: A systematic literature search was conducted using PubMed. A total of 19 studies with 316,178 adult participants were included. Results: Eleven of the sixteen studies concentrating on the prevalence of glaucoma in patients with OSA showed an association of both entities. One paper found a higher risk for progression of glaucoma in OSA patients. Five of the sixteen included studies failed to show a correlation between OSA and glaucoma. One study out of three surveying specific ophthalmological parameters showed an influence of OSA therapy on retinal nerve fiber layer (RNFL) thinning and vision. One study showed a rise in intraocular pressure (IOP), while two other studies showed no increase under continuous positive airway pressure (CPAP). Conclusions: Our findings suggest an association between OSA and glaucoma and, especially, between OSA and thinning of RNFL. CPAP therapy appears to be also suitable for patients with comorbid glaucoma. Full article

(This article belongs to the Special Issue Sleep Apnea and Intermittent Hypoxia 3.0)

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