The efficacy of obstructive sleep apnea (OSA) therapy with continuous positive airway pressure (CPAP) on uric acid (UA) yielded conflicting results. This meta-analysis was performed to assess whether OSA treatment with CPAP could reduce UA levels.

Tissue hypoxia caused by upper airway collapse is a main cause of excessive oxidative stress and systemic inflammation in obstructive sleep apnea (OSA) patients. Increased reactive oxygen species (ROS) and inflammatory responses affect cell survival and ultimately contribute to tissue injury. In the present study, we proposed that the induction of ROS by hypoxia, as an intrinsic stress, activates myoblast pyroptosis in OSA. We found increased cell death and abnormal expression of pyroptosis markers in the skeletal muscle of OSA mice. In vitro studies showed hypoxia-induced pyroptotic death of C2C12 myoblasts, as evidenced by the activation of caspase-1 and gasdermin D (GSDMD). Hypoxia induced ROS overproduction and accumulation in myoblasts. More importantly, applying N-acetylcysteine (NAC), an ROS scavenger, rescued cell swelling, downregulated the inflammatory response, and prevented pyroptotic death in hypoxia-cultured myoblasts. Hypoxia stimulation promoted NF-κB P65 phosphorylation and HIF-1α nuclear translocation. Moreover, hypoxia increased the nuclear level of cleaved caspase-1 and GSDMD. NAC inhibited hypoxia-induced variations in the HIF-1α and NF-κB signaling pathway. Taken together, our results determined that hypoxia-induced ROS contribute to myoblast pyroptosis. Therefore, our findings suggest that ROS may be a potential therapeutic target for ameliorating hypoxia-induced cell death and tissue injury, especially in OSA and hypoxia-related diseases.

The present study investigated the nuclear factor erythroid 2-related factor 2- (Nrf2-) antioxidant response element (ARE) signaling pathway in patients with moderate to severe obstructive sleep apnea-hypopnea syndrome (OSAHS). Their correlation with neurocognitive impairment metrics was investigated to explore potential pathogenesis in OSAHS. Forty-eight patients with OSAHS and 28 controls underwent testing with the Epworth Sleep Scale (ESS), MATRICS Consensus Cognitive Battery (MCCB), Stroop Color and Word Test, polysomnography (PSG), and measurements of the concentration of plasma superoxide dismutase (SOD) and thioredoxin (Trx). Further, 20 pairs of matched patients with OSAHS and controls were selected for measurement of the expression (protein and mRNA) of Nrf2 and of its downstream antioxidase, heme oxygenase-1 (HO-1), in peripheral mononuclear cells (PBMCs). Finally, correlations between neurocognitive impairment and the above metrics were analyzed. Expression of Nrf2 and HO-1 mRNA and protein in the PBMCs, as well as plasma SOD and Trx levels, were significantly reduced in patients with OSAHS. After adjusting for education, sex, age, and smoking index, the expression of Nrf2-ARE signaling pathway proteins (or mRNA) was closely correlated with sleep respiratory parameters. An inverse relationship was demonstrated between the expression of nuclear Nrf2 in PBMCs, concentration of plasma SOD and Trx, and apnea-hypopnea index (AHI) in patients with OSAHS. Trx, nuclear Nrf2 protein, and HO-1 protein were also negatively correlated with the percent of time that SaO2 was less than 90% (TSat90). Total Nrf2 protein level was positively correlated with AHI and TSat90 and negatively correlated with minimum SaO2 (LSaO2), while nuclear Nrf2 protein and HO-1 protein were positively correlated with LSaO2. Moreover, significant positive correlations were found between maze scores and expression of nuclear Nrf2 protein, HO-1 protein, and SOD and Trx levels. Furthermore, inverse relationships between total Nrf2 protein in PBMCs and HVLT-R and maze scores were found. Multiple linear regression showed plasma Trx concentration as a potential predictor of maze and BVMT-R scores. In conclusion, the expression of Nrf2-ARE molecules and related antioxidases is significantly decreased in patients with OSAHS and is correlated with neurocognitive dysfunction. The Nrf2-ARE signaling pathway may play a crucial role in neurocognitive impairment in patients with moderate to severe OSAHS. Further studies are needed to explore the exact mechanisms and potential treatment interventions.

Severe obstructive sleep apnea (OSA) with chronic intermittent hypoxia (IH) is common in idiopathic pulmonary fibrosis (IPF). Here, we evaluated the impact of IH on bleomycin- (BLM-) induced pulmonary fibrosis in mice.

Obstructive sleep apnea (OSA) is characterized by recurrent airway collapse that causes chronic intermittent hypoxia (CIH). OSA is associated with systemic inflammation and oxidative stress resulting in endothelial dysfunction and cardiovascular disease (CVD). Alpha lipoic acid (ALA) is a potent antioxidant with anti-inflammatory properties. We hypothesized that dietary ALA can improve endothelial function of mice exposed to CIH.

Because the function and mechanisms of sleep are partially clear, here we applied a meta-analysis to address the issue whether sleep function includes antioxidative properties in mice and rats. Given the expansion of the knowledge in the sleep field, it is indeed ambitious to describe all mammals, or other animals, in which sleep shows an antioxidant function. However, in this paper we reviewed the current understanding from basic studies in two species to drive the hypothesis that sleep is a dynamic-resting state with antioxidative properties. We performed a systematic review of articles cited in Medline, Scopus, and Web of Science until March 2015 using the following search terms: Sleep or sleep deprivation and oxidative stress, lipid peroxidation, glutathione, nitric oxide, catalase or superoxide dismutase. We found a total of 266 studies. After inclusion and exclusion criteria, 44 articles were included, which are presented and discussed in this study. The complex relationship between sleep duration and oxidative stress is discussed. Further studies should consider molecular and genetic approaches to determine whether disrupted sleep promotes oxidative stress.

Oxidative stress is involved in the development of carotid body (CB) chemosensory potentiation and systemic hypertension induced by chronic intermittent hypoxia (CIH), the main feature of obstructive sleep apnea. We tested whether peroxynitrite (ONOO(-)), a highly reactive nitrogen species, is involved in the enhanced CB oxygen chemosensitivity and the hypertension during CIH. Accordingly, we studied effects of Ebselen, an ONOO(-) scavenger, on 3-nitrotyrosine immunoreactivity (3-NT-ir) in the CB, the CB chemosensory discharge, and arterial blood pressure (BP) in rats exposed to CIH. Male Sprague-Dawley rats were exposed to CIH (5% O2, 12 times/h, 8 h/day) for 7 days. Ebselen (10 mg/kg/day) was administrated using osmotic minipumps and BP measured with radiotelemetry. Compared to the sham animals, CIH-treated rats showed increased 3-NT-ir within the CB, enhanced CB chemosensory responses to hypoxia, increased BP response to acute hypoxia, and hypertension. Rats treated with Ebselen and exposed to CIH displayed a significant reduction in 3-NT-ir levels (60.8 ± 14.9 versus 22.9 ± 4.2 a.u.), reduced CB chemosensory response to 5% O2 (266.5 ± 13.4 versus 168.6 ± 16.8 Hz), and decreased mean BP (116.9 ± 13.2 versus 82.1 ± 5.1 mmHg). Our results suggest that CIH-induced CB chemosensory potentiation and hypertension are critically dependent on ONOO(-) formation.

Obstructive sleep apnea (OSA), characterized by intermittent hypoxia (IH), is associated with obesity and metabolic disorders. The mass and function of adipose tissue are largely dependent on adipogenesis. The impact of low-frequency IH on adipogenesis is unknown. Sprague-Dawley rats were subjected to IH (4 min for 10% O2 and 2 min for 21% O2) or intermittent normoxia (IN) for 6 weeks. The degree of adipogenic differentiation was evaluated by adipogenic transcriptional factors, adipocyte-specific proteins, and oily droplet production in both subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT). Upregulation of proadipogenic markers (CEBPα, PPARγ, and FABP4) and downregulation of antiadipogenic markers CHOP in line with smaller size of adipocytes were found in IH-exposed SAT. In vitro experiments using human preadipocytes (HPAs) of subcutaneous lineage during differentiation phase, subjected to IH (1% O2 for 10 min and 21% O2 for 5 min; 5% CO2) or IN treatment, were done to investigate the insulin-like growth factor 1 receptor (IGF-1R)/Akt pathway in adipogenesis. IH promoted the accumulation of oily droplets and adipogenesis-associated markers. IGF-1R kinase inhibitor NVP-AEW541 attenuated the proadipogenic role in IH-exposed HPAs. In summary, relatively low frequency of IH may enhance adipogenesis preferentially in SAT.

Obstructive sleep apnea (OSA) associated chronic kidney disease is mainly caused by chronic intermittent hypoxia (CIH) triggered tissue damage. Receptor for advanced glycation end product (RAGE) and its ligand high mobility group box 1 (HMGB1) are expressed on renal cells and mediate inflammatory responses in OSA-related diseases. To determine their roles in CIH-induced renal injury, soluble RAGE (sRAGE), the RAGE neutralizing antibody, was intravenously administered in a CIH model. We also evaluated the effect of sRAGE on inflammation and apoptosis. Rats were divided into four groups: (1) normal air (NA), (2) CIH, (3) CIH+sRAGE, and (4) NA+sRAGE. Our results showed that CIH accelerated renal histological injury and upregulated RAGE-HMGB1 levels involving inflammatory (NF-κB, TNF-α, and IL-6), apoptotic (Bcl-2/Bax), and mitogen-activated protein kinases (phosphorylation of P38, ERK, and JNK) signal transduction pathways, which were abolished by sRAGE but p-ERK. Furthermore, sRAGE ameliorated renal dysfunction by attenuating tubular endothelial apoptosis determined by immunofluorescence staining of CD31 and TUNEL. These findings suggested that RAGE-HMGB1 activated chronic inflammatory transduction cascades that contributed to the pathogenesis of the CIH-induced renal injury. Inhibition of RAGE ligand interaction by sRAGE provided a therapeutic potential for CIH-induced renal injury, inflammation, and apoptosis through P38 and JNK pathways.

Objective. Obstructive sleep apnea (OSA), characterized by chronic intermittent hypoxia (CIH), is often present in diabetic (DB) patients. Both conditions are associated with endothelial dysfunction and cardiovascular disease. We hypothesized that diabetic endothelial dysfunction is further compromised by CIH. Methods. Adult male diabetic (BKS.Cg-Dock7m +/+ Leprdb /J) (db/db) mice (10 weeks old) and their heterozygote littermates were subjected to CIH or intermittent air (IA) for 8 weeks. Mice were separated into 4 groups: IA (intermittent air nondiabetic), IH (intermittent hypoxia nondiabetic), IADB (intermittent air diabetic), and IHDB (intermittent hypoxia diabetic) groups. Endothelium-dependent and endothelium-independent relaxation and modulation by basal nitric oxide (NO) were analyzed using wire myograph. Plasma 8-isoprostane, interleukin-6 (IL-6), and asymmetric dimethylarginine (ADMA) were measured using ELISA. Uncoupling of eNOS was measured using dihydroethidium (DHE) staining. Results. Endothelium-dependent vasodilation and basal NO production were significantly impaired in the IH and IADB group compared to IA group but was more pronounced in IHDB group. Levels of 8-isoprostane, IL-6, ADMA, and eNOS uncoupling were ≈2-fold higher in IH and IADB groups and were further increased in the IHDB group. Conclusion. Endothelial dysfunction is more pronounced in diabetic mice subjected to CIH compared to diabetic or CIH mice alone. Oxidative stress, ADMA, and eNOS uncoupling were exacerbated by CIH in diabetic mice.

Obstructive sleep apnea (OSA) can cause intermittent changes in blood oxygen saturation, resulting in the generation of many reactive oxygen species (ROS). To discover new antioxidants and clarify the endoplasmic reticulum (ER) stress involved in cardiac injury in OSA, we established a chronic intermittent hypoxia (CIH) rat model with a fraction of inspired O2 (FiO2) ranging from 21% to 9%, 20 times/h for 8 h/day, and the rats were treated with H2-O2 mixture (67% hydrogen and 33% oxygen) for 2 h/day for 35 days. Our results showed that H2-O2 mixture remarkably improved cardiac dysfunction and myocardial fibrosis. We found that H2-O2 mixture inhalation declined ER stress-induced apoptosis via three major response pathways: PERK-eIF2α-ATF4, IRE 1-XBP1, and ATF 6. Furthermore, we revealed that H2-O2 mixture blocked c-Jun N-terminal kinase- (JNK-) MAPK activation, increased the ratio of Bcl-2/Bax, and inhibited caspase 3 cleavage to protect against CIH-induced cardiac apoptosis. In addition, H2-O2 mixture considerably decreased ROS levels via upregulating superoxide dismutase (SOD) and glutathione (GSH) as well as downregulating NADPH oxidase (NOX 2) expression in the hearts of CIH rats. All the results demonstrated that H2-O2 mixture significantly reduced ER stress and apoptosis and that H2 might be an efficient antioxidant against the oxidative stress injury induced by CIH.

Although chronic intermittent hypoxia- (IH-) induced myocardial apoptosis is an established pathophysiological process resulting in a poor prognosis for patients with obstructive sleep apnea syndrome, its underlying mechanism remains unclear. This study is aimed at exploring the role of makorin ring finger protein 1 (MKRN1) in IH-induced myocardial apoptosis and elucidating its molecular activity. First, the GSE2271 dataset was downloaded from the Gene Expression Omnibus database to identify the differentially expressed genes. Then, an SD rat model of IH, together with rat cardiomyocyte H9C2 and human cardiomyocyte AC16 IH models, was constructed. TUNEL, Western blot, and immunohistochemistry assays were used to detect cell apoptosis. Dihydroethidium staining was conducted to analyze the concentration of reactive oxygen species. In addition, RT-qPCR, Western blot, and immunohistochemistry were performed to measure the expression levels of MKRN1 and p21. The direct interaction between MKRN1 and p21 was determined using coimmunoprecipitation and ubiquitination analysis. MKRN1 expression was found to be downregulated in IH rat myocardial tissues as well as in H9C2 and AC16 cells. Upregulated expression of MKRN1 in H9C2 and AC16 cells alleviated the IH-induced reactive oxygen species production and cell apoptosis. Mechanistically, MKRN1 promoted p21 protein ubiquitination and the proteasome pathway degradation to negatively regulate p21 expression. Thus, MKRN1 regulates p21 ubiquitination to prevent IH-induced myocardial apoptosis.

Obstructive sleep apnea (OSA) patients exhibit different degrees of cognitive impairment, which is related to the activation of reactive oxygen species (ROS) production by chronic intermittent hypoxia (CIH) and the deposition of iron in the brain. As a central regulator of iron homeostasis, whether hepcidin is involved in OSA-induced cognitive impairment has not been clarified. In order to simulate OSA, we established the mouse model by reducing the percentage of inspired O2 (FiO2) from 21% to 5%, 20 times/h for 8 h/day. We found hepcidin was rising during CIH, along with increasing iron levels and neuron loss. Then, we constructed a mouse with astrocyte-specific knockdown hepcidin gene (shHamp). During CIH exposure, the shHamp mice showed a lower level of total iron and neuronal iron in the hippocampus, via stabilizing ferroportin 1 (FPN1) and decreasing L-ferritin (FTL) levels, when compared with wild-type (WT) mice. Furthermore, the shHamp mice showed a decrease of ROS by downregulating the elevated NADPH oxidase (NOX2) and 4-hydroxynonenal (4-HNE) levels mediated by CIH. In addition, the shHamp mice presented improved cognitive deficit by improving synaptic plasticity and BDNF expression in the hippocampus when subjected to CIH. Therefore, our data revealed that highly expressed hepcidin might promote the degradation of FPN1, resulting in neuronal iron deposition, oxidative stress damage, reduced synaptic plasticity, and impaired cognitive performance during CIH exposure.

MicroRNAs (miRNAs) have emerged as key modulators in the pathophysiologic processes of cardiovascular diseases. However, its function in cardiac injury induced by obstructive sleep apnea (OSA) remains unknown. The aim of the current study was to identify the effect and potential molecular mechanism of miR-146a-5p in intermittent hypoxia(IH)- induced myocardial damage. We exposed H9c2 cells to IH condition; the expression levels of miR-146a-5p were detected by RT-qPCR. Cell viability, cell apoptosis, and the expressions of apoptosis-associated proteins were assessed via Cell Counting Kit-8 (CCK-8), flow cytometry, and western blotting, respectively. Target genes of miR-146a-5p were confirmed by dual-luciferase reporter assay. IH remarkably lowered viability but enhanced cell apoptosis. Concomitantly, the miR-146a-5p expression level was increased in H9c2 cells after IH. Subsequent experiments showed that IH-induced injury was alleviated through miR-146a-5p silence. X-linked inhibitor of apoptosis protein (XIAP) was predicted by bioinformatics analysis and further confirmed as a direct target gene of miR-146a-5p. Surprisingly, the effect of miR-146a-5p inhibition under IH may be reversed by downregulating XIAP expression. In conclusion, our results demonstrated that miR-146a-5p could attenuate viability and promote the apoptosis of H9c2 by targeting XIAP, thus aggravating the H9c2 cell injury induced by IH, which could enhance our understanding of the mechanisms for OSA-associated cardiac injury.

This study investigated the effects of chronic intermittent hypoxia (CIH), a model of sleep apnea syndrome (SAS), on cardiac function. SRC-3 was extremely lowly expressed in the adult mouse heart tissue, while SRC-3 was highly expressed in the adult mouse heart tissue after CIH, suggesting that SRC-3 is involved in CIH model. We further studied the role of SRC-3 in CIH-induced myocardial injury in mice. Twenty-four healthy Balb/c male mice (n = 16, wild type; n = 8, SRC-3 knockout (SRC3-KO)) were randomly divided into three groups: air control (Ctrl), CIH, and CIH+SRC3-KO. Mice were exposed to CIH for 12 weeks. qRT-PCR was used to evaluate cardiac expression of the following genes: 11HSD1, 11HSD2, GR, MR, COX-2, OPN, NOX2, HIF-1-α, IL-1β, IL-6, iNOS, TNF-α, PC-1, and TGF-β. Enzymatic levels of SOD, CAT, MDA, NOS, and NO in the mouse hearts were determined using commercially available kits. Immunohistochemistry (IHC) was used to evaluate NF-κB expression in cardiac tissues. A transmission electron microscope (TEM) was used to evaluate myocardial ultrastructure. TUNEL staining was used to assess myocardial cell apoptosis. CIH induced cardiac damage, which was ameliorated in the SRC-3 KO mice. CIH significantly increased the heart-to-body weight ratio, expression of all aforementioned genes except 11HSD1, GR, and MR, and increased the levels of MDA, NOS, NO, and NF-κB, which were attenuated in the SRC-3 KO mice. The CIH group had the lowest SOD and CAT levels, which were partially recovered in the CIH+SRC3-KO group. 11HSD2 gene expression was elevated in both the CIH and CIH+SRC3-KO groups compared to the Ctrl group. The CIH group had severe myocardial cell apoptosis and mitochondrial dysfunction, which were alleviated in the CIH+SRC3-KO group. CIH causes cardiac damage through inducing oxidative stress and inflammation. Knockout of SRC-3 ameliorates CIH-induced cardiac damage through antagonizing CIH-triggered molecular changes in cardiac tissue.

Hypoxic pulmonary vascular remodelling (PVR) is the major pathological basis of aging-related chronic obstructive pulmonary disease and obstructive sleep apnea syndrome. The pulmonary artery endothelial cell (PAEC) inflammation, and pulmonary artery smooth muscle cell (PASMC) proliferation, hypertrophy and collagen remodelling are the important pathophysiological components of PVR. Endogenous sulfur dioxide (SO2) was found to be a novel gasotransmitter in the cardiovascular system with its unique biological properties. The study was aimed to investigate the role of endothelial cell- (EC-) derived SO2 in the progression of PAEC inflammation, PASMC proliferation, hypertrophy and collagen remodelling in PVR and the possible mechanisms. EC-specific aspartic aminotransferase 1 transgenic (EC-AAT1-Tg) mice were constructed in vivo. Pulmonary hypertension was induced by hypoxia. Right heart catheterization and echocardiography were used to detect mouse hemodynamic changes. Pathologic analysis was performed in the pulmonary arteries. High-performance liquid chromatography was employed to detect the SO2 content. Human PAECs (HPAECs) with lentiviruses containing AAT1 cDNA or shRNA and cocultured human PASMCs (HPASMCs) were applied in vitro. SO2 probe and enzyme-linked immunosorbent assay were used to detect the SO2 content and determine p50 activity, respectively. Hypoxia caused a significant reduction in SO2 content in the mouse lung and HPAECs and increases in right ventricular systolic pressure, pulmonary artery wall thickness, muscularization, and the expression of PAEC ICAM-1 and MCP-1 and of PASMC Ki-67, collagen I, and α-SMA (p < 0.05). However, EC-AAT1-Tg with sufficient SO2 content prevented the above increases induced by hypoxia (p < 0.05). Mechanistically, EC-derived SO2 deficiency promoted HPAEC ICAM-1 and MCP-1 and the cocultured HPASMC Ki-67 and collagen I expression, which was abolished by andrographolide, an inhibitor of p50 (p < 0.05). Meanwhile, EC-derived SO2 deficiency increased the expression of cocultured HPASMC α-SMA (p < 0.05). Taken together, these findings revealed that EC-derived SO2 inhibited p50 activation to control PAEC inflammation in an autocrine manner and PASMC proliferation, hypertrophy, and collagen synthesis in a paracrine manner, thereby inhibiting hypoxic PVR.