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The state-dependent noradrenergic activation of hypoglossal motoneurons plays an important role in the maintenance of upper airway patency and pathophysiology of obstructive sleep apnea (OSA). Chronic intermittent hypoxia (CIH), a major pathogenic factor of OSA, contributes to the risk for developing neurodegenerative disorders in OSA patients. Using anterograde tracer, channelrhodopsin-2, we mapped axonal projections from noradrenergic A7 and SubCoeruleus neurons to hypoglossal nucleus in DBH-cre mice and assessed the effect of CIH on these projections. We found that CIH significantly reduced the number of axonal projections from SubCoeruleus neurons to both dorsal (by 68%) and to ventral (by73%) subregions of the hypoglossal motor nucleus compared to sham-treated animals. The animals' body weight was also negatively affected by CIH. Both effects, the decrease in axonal projections and body weight, were more pronounced in male than female mice, which was likely caused by less sensitivity of female mice to CIH as compared to males. The A7 neurons appeared to have limited projections to the hypoglossal nucleus. Our findings suggest that CIH-induced reduction of noradrenergic innervation of hypoglossal motoneurons may exacerbate progression of OSA, especially in men.

Obstructive sleep apnea (OSA) is a common respiratory disorder, primarily characterized by two pathological features: chronic intermittent hypoxia (CIH) and sleep deprivation (SD). OSA has been identified as a risk factor for numerous diseases, and the inflammatory response related to programmed cell necrosis is believed to play a significant role in the occurrence and progression of multisystem damage induced by OSA, with increasing attention being paid to pyroptosis. Recent studies have indicated that OSA can elevate oxidative stress levels in the body, activating the process of pyroptosis within different tissues, ultimately accelerating organ dysfunction. However, the molecular mechanisms of pyroptosis in the multisystem damage induced by OSA remain unclear. Therefore, this review focuses on four major systems that have received concentrated attention in existing research in order to explore the role of pyroptosis in promoting renal diseases, cardiovascular diseases, neurocognitive diseases, and skin diseases in OSA patients. Furthermore, we provide a comprehensive overview of methods for inhibiting pyroptosis at different molecular levels, with the goal of identifying viable targets and therapeutic strategies for addressing OSA-related complications. [ABSTRACT FROM AUTHOR]

Purpose: This study investigated the prevalence of non-alcoholic fatty pancreatic disease (NAFPD) in patients with obstructive sleep apnoea (OSA) and analysed the correlation between them. Materials and methods: Patients who underwent polysomnography and modified abdominal ultrasound examinations were continuously enrolled and divided into OSA and control groups. The OSA group was further divided into NAFPD and non-NAFPD groups. Differences in various indicators were compared. Binary logistic regression analyses were conducted to identify factors influencing NAFPD. Results: A total of 210 participants were included in the study, including 178 in the OSA group and 32 in the control group. The prevalence of NAFPD, weight, body mass index (BMI), and other indicators were significantly higher in the OSA group than that in the control group (p < 0.05). The above indices, prevalence of hypertension and metabolic associated steatotic liver disease (MASLD), and severity of sleep apnoea were higher in the NAFPD group than that in the non-NAFPD group (p < 0.05). Binary logistic regression analysis showed a 4.4% increased risk of NAFPD for each unit increase in apnea-hypopnea index (AHI) after adjusting for BMI and hypertension. Conclusion: The prevalence of NAFPD was higher in the OSA group than that in the control group, and chronic intermittent hypoxia was strongly associated with pancreatic fat infiltration; AHI, BMI, and hypertension were independent risk factors for NAFPD. The NAFPD group had a higher prevalence of obesity and some other diseases. STATEMENT OF SIGNIFICANCE: This study confirms that the modified ultrasound evaluation method can serve as an effective tool for screening pancreatic fat infiltration in OSA patients, aiding in the early identification of the risk of ectopic lipid deposition and metabolic excess. [ABSTRACT FROM AUTHOR]

Aim: Obstructive sleep apnea (OSA) is a growing health problem affecting nearly 1 billion people worldwide. The landmark feature of OSA is chronic intermittent hypoxia (CIH), accounting for multiple organ damage, including heart disease. CIH profoundly alters both visceral white adipose tissue (WAT) and heart structure and function, but little is known regarding inter‐organ interaction in the context of CIH. We recently showed that visceral WAT senescence drives myocardial alterations in aged mice without CIH. Here, we aimed at investigating whether CIH induces a premature visceral WAT senescent phenotype, triggering subsequent cardiac remodeling. Methods: In a first experiment, 10‐week‐old C57bl6J male mice (n = 10/group) were exposed to 14 days of CIH (8 h daily, 5%–21% cyclic inspired oxygen fraction, 60 s per cycle). In a second series, mice were submitted to either epididymal WAT surgical lipectomy or sham surgery before CIH exposure. Finally, we used p53 deficient mice or Wild‐type (WT) littermates, also exposed to the same CIH protocol. Epididymal WAT was assessed for fibrosis, DNA damages, oxidative stress, markers of senescence (p16, p21, and p53), and inflammation by RT‐qPCR and histology, and myocardium was assessed for fibrosis and cardiomyocyte hypertrophy. Results: CIH‐induced epididymal WAT remodeling characterized by increased fibrosis, oxidative stress, DNA damage response, inflammation, and increased expression of senescent markers. CIH‐induced epididymal WAT remodeling was associated with subtle and early myocardial interstitial fibrosis. Both epididymal WAT surgical lipectomy and p53 deletion prevented CIH‐induced myocardial fibrosis. Conclusion: Short‐term exposure to CIH induces epididymal WAT senescent remodeling and cardiac interstitial fibrosis, the latter being prevented by lipectomy. This finding strongly suggests visceral WAT senescence as a new target to mitigate OSA‐related cardiac disorders. [ABSTRACT FROM AUTHOR]

Objective To investigate the efiect and mechanism of Jiawei Ditan Decoction on cardiomyocyte ierroptosis in rats with chronic intermittent hypoxia based on the phosphoinositide 3-kinase (PI3K) /protein kinase B ( Akt) signaling pathway. Methods Thirty 8-week-old male Sprague-Dawley rats were randomly divided into normal control, low-oxygen intervention, and Jiawei Ditan Decoction intervention groups using the random number table method, with 10 rats per group. The low-oxygen and Jiawei Ditan Decoction intervention groups were treated with intermittent hypoxia chamber for modeling, with 8 h of intervention daily. Gavage administration was performed before and after daily intervention. The intervention group received a dosage of 16. 38 g/kg Jiawei Ditan Decoction, whereas the other two groups received normal saline. The experimental intervention period was 12 weeks. Hematoxylin and eosin staining was used to observe the morphology of myocardial tissue. Transmission electron microscope was used to observe the mitochondrial ultrastructure in cardiomyocytes. Biochemical detection was used to measure the Fe2+ and malondialdehyde ( MDA ) content in myocardial tissue. Phosphorylated-phosphoinositide 3-kinase ( p-PI3K), PI3K, phosphorylated-protein kinase B ( p-Akt), Akt, solute carrier family 7 member 11 (SLC7A11), glutathione peroxidase 4 ( GPX4), nuclear factor erythroid 2-related factor 2 ( Nrf2), and acyl-coenzyme A synthetase long-chain family member 4 ( ACSL4) protein expression in myocardial tissue were measured using western blotting. The rat cardiomyocyte cell line, H9c2, was cultured in high glucose Dulbecco's Modified Eagle Medium, and the ultra-high-performance liquid chromatography was used to detect drug components in Jiawei Ditan Decoction. The CCK-8 assay was used to detect the cell survival rate of cells treated with different concentrations of Jiawei Ditan Decoction. The cells were divided into the normoxic, erastin, and erastin + Jiawei Ditan Decoction intervention groups, and p-Akt and GPX4 protein expression was measured using western blotting. p-PI3K and GPX4 protein expression were detected in the normoxic, low-oxygen intervention 12 h, and low-oxygen intervention 12 h + 740Y-P groups. The p-PI3K, PI3K, p-Akt, Akt, and GPX4 protein expression was detected in the normoxic, low-oxygen intervention 6 h, low-oxygen intervention 12 h, low-oxygen intervention 12 h + Jiawei Ditan Decoction low-dose, low-oxygen intervention 12 h + Jiawei Ditan Decoction medium-dose, and low-oxygen intervention 12 h + Jiawei Ditan Decoction high-dose groups (drug concentrations of 5, 10, and 20 g/L, respectively). Results The myocardial cells in the low-oxygen intervention group were disordered and swollen and the mitochondrial arrangement of myocardial cells was disordered, with increased mitochondrial membrane density, ruptured cristae, and vacudar degeneration compared with those in the normal control group. The myocardial cells in the Jiawei Ditan Decoction intervention group were arranged neater, and the morphology of mitochondria was relatively regular than those in the low-oxygen intervention group, and no apparent swelling was observed. Compared with the normal control group, the low-oxygen intervention group showed an increase in the MDA and Fe2+ content, a decrease in the p-PI3K/PI3K and p-Akt/Akt values, decreased SLC7A11, GPX4, and Nrf2 expression, and increased ACSL4 expression ( P <0.05). Compared with the low-oxygen intervention group, the Jiawei Ditan Decoction intervention group showed a decrease in MDA and Fe2+ content, an increase in the p-PI3K/PI3K and p-Akt/Akt values, increased SLC7A11, GPX4, and Nrf2 expression, and decreased ACSL4 expression ( P <0.05). Jiawei Ditan Decoction contained DL-stachydrine, D-( +) -malicacid, adenosine, etc. The cell survival rate of the 10. 00 g/L group increased (P<0.05) compared to that of the Jiawei Ditan Decoction 0, 1.25, 2.50, 5. 00, and 20. 00 g/L groups. Compared with the normoxic group, p-Akt and GPX4 expression decreased in the erastin group (P<0.05) ； compared with the erastin group, the erastin + Jiawei Ditan Decoction intervention group showed increased p-Akt and GPX4 expression ( P<0. 05). Compared with the normoxic group, p-PI3K and GPX4 expression decreased in the low-oxygen intervention 12 h group ( P<0. 01) ； compared with the low-oxygen intervention 12 h group, the low-oxygen intervention 12 h + 740Y-P group showed increased p-PI3K and GPX4 expression ( P<0. 05). Compared with the normoxic group, GPX4 expression and the p-Akt/Akt and p-PI3K/PI3K were reduced in the low-oxygen intervention 6 and 12 h groups ( P < 0. 05) ; compared with the low-oxygen intervention 6 h and 12 h groups, the p-PI3K/PI3K and p-Akt/Akt values increased in the low-oxygen intervention 12 h + Jiawei Ditan Decoction low, medium, and high-dose groups ( P<0. 05). GPX4 expression was also increased ( P<0. 05). Conclusion Jiawei Ditan Decoction may improve cardiomyocyte ierroptosis in rats by regulating the PI3K/Akt signaling pathway, thereby playing a protective role against chronic intermittent hypoxia-induced cardiac injury in rats. [ABSTRACT FROM AUTHOR]

Aims: Hydrogen sulfide (H2S) is a novel gas signaling molecule that has been researched in several physiological and pathological conditions, indicating that strategies targeting H2S may provide clinical benefits in diseases such as chronic cardiomyopathy. Here, we reveal the effect of H2S on chronic intermittent hypoxia (CIH)-related myocardial damage and its mechanistic relevance to phosphoinositol-3 kinase (PI3K). Materials: Mice were subjected to a 4-week CIH process to induce myocardial damage, which was accompanied by daily administration of NaHS (a H2S donor) and LY294002 (an inhibitor of PI3K). Changes in heart function were evaluated via echocardiography. Histological examination was applied to assess heart tissue lesions. Myocardial apoptosis was detected by TUNEL staining and apoptosis-associated protein expression. Furthermore, the effects of NaHS on autophagy and the PI3K/AKT/mTOR pathway were investigated. Finally, the level of inflammation is also affected by related proteins. Key findings: The CIH group presented increased myocardial dysfunction and heart tissue lesions. Echocardiography and histological analysis revealed that, compared with control mice, CIH-treated mice presented significantly more severe left ventricular remodeling and decreased myocardial contractile function. In addition, the apoptosis index and oxidative markers were significantly elevated in the CIH group compared with those in the control group. The autophagy marker Beclin-1 was decreased, while p62 was elevated by CIH treatment. H2S supplementation with NaHS significantly improved cardiac function and alleviated fibrosis, oxidative stress, and apoptosis but upregulated autophagy in CIH mice, and these effects were also observed in animals that underwent only PI3K blockade. Furthermore, PI3K/AKT pathway-mediated inhibition of the mammalian target of rapamycin (mTOR) pathway, the Nrf2/HO-1 pathway and proinflammatory NF-κB activity were shown to play a role in the therapeutic effect of NaHS after CIH stimulation.Significance: NaHS supplementation during CIH reversed myocardial damage by targeting the PI3K/AKT/mTOR pathway, which appears to indicate that interventions targeting endogenous H2S have significant clinical implications for the stabilization of cardiac function in extreme cases. [ABSTRACT FROM AUTHOR]

Kai-li Liu,&ast; Shen-jie Xu,&ast; Si-wen Chen, Min-jie Zhang, Ni Ye, Jie Li Department of General Medicine, The First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jie Li; Ni Ye, Department of General Medicine, The First Affiliated Hospital of Soochow University, No. 899 of Pinghai Road, Gusu District, Suzhou, 215006, People’s Republic of China, Tel: +86 139 6211 6580 ; +86 151 6246 0064, Email lijie_Li01@126.com; yeni0328@126.comObjective: The aim of this study was to analyze the relationship between the characteristics of the intestinal microbiota and cytokine levels in individuals with different degrees of obstructive sleep apnea-hypopnea syndrome (OSAHS) as well as to investigate intestinal microbiota imbalances in patients with OSAHS and the associated mechanisms.Methods: Based on their sleep apnea hypopnea index (AHI), a total of 37 adults were assigned to a control group, a mild OSAHS group, or a moderate-to-severe OSAHS group. Fecal samples were collected to characterize the intestinal microbiota using metagenomic next-generation sequencing (mNGS), while blood samples were collected to detect levels of interleukin-17a (IL-17a), interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) in each group.Results: 1. There was no significant difference in the Shannon index among the three groups (P > 0.05). The three groups showed significant difference in the relative abundance of Faecalibacterium prausnitzii and Bifidobacterium adolescentis (with F values of 3.955 and 7.24, respectively, P < 0.05), while showed no significant difference in the relative abundance of B. pseudocatenulatum, Bifidobacterium longum, Klebsiella pneumoniae, and Haemophilus parainfluenzae (P > 0.05). 2. The three groups showed significant difference in the expression of serum IL-17A and TNF-α levels (with F values of 18.119 and 10.691, respectively, P < 0.05), while showed no significant difference in the expression of IL-10, IL-6, and CRP levels (P > 0.05). 3. Multiple linear regression analysis revealed that the relative abundance of F. prausnitzii was correlated with changes in BMI and AHI (with β values of 2.585 and − 0.157, respectively, P < 0.05), while the relative abundance of B. adolescentis was correlated with changes in IL-17a (with β value of − 0.161, P < 0.05).Conclusion: The study revealed a significant correlation between intestinal microbiota abundance and cytokine levels, suggesting that gut microbiota disruption in OSAHS patients may be linked to systemic chronic inflammation.Keywords: chronic inflammation, chronic intermittent hypoxia, cytokines, intestinal microbiota, OSAHS

Abstract Background Obstructive sleep apnea (OSA), characterized by chronic intermittent hypoxia (CIH), is a prevalent condition that has been associated with various forms of cancer. Although some clinical studies suggest a potential link between OSA and lung cancer, this association remains uncertain, and the underlying mechanisms are not fully understood. This study investigated the role of the catecholamine-β-adrenergic receptor (βAR) and the NLRP3 inflammasome in mediating the effects of CIH on lung cancer progression in mice. Methods Male C57BL/6 N mice were subjected to CIH for four weeks, with Lewis lung carcinoma cells seeded subcutaneously. Propranolol (a βAR blocker) or nepicastat (an inhibitor of catecholamine production) was administered during this period. Tumor volume and tail artery blood pressure were monitored. Immunohistochemical staining and immunofluorescence staining were employed to assess protein expression of Ki-67, CD31, VEGFR2, PD-1, PD-L1, and ASC specks in tumor tissues. ELISA was used to detect catecholamine and various cytokines, while western blot assessed the expression of cyclin D1, caspase-1, and IL-1β. In vitro tube formation assay investigated angiogenesis. NLRP3 knockout mice were used to determine the mechanism of NLRP3 in CIH. Results CIH led to an increase in catecholamine. Catecholamine-βAR inhibitor drugs prevented the increase in blood pressure caused by CIH. Notably, the drugs inhibited CIH-induced murine lung tumor growth, and the expression of Ki-67, cyclin D1, CD31, VEGFR2, PD-1 and PD-L1 in tumor decreased. In vitro, propranolol inhibits tube formation induced by CIH mouse serum. Moreover, CIH led to an increase in TNF-α, IL-6, IL-1β, IFN-γ and sPD-L1 levels and a decrease in IL-10 in peripheral blood, accompanied by activation of NLRP3 inflammasomes in tumor, but these effects were also stopped by drugs. In NLRP3-knockout mice, CIH-induced upregulation of PD-1/PD-L1 in tumor was inhibited. Conclusions Our study underscores the significant contribution of β-adrenergic signaling and the NLRP3 inflammasome to CIH-induced lung cancer progression. These pathways represent potential therapeutic targets for mitigating the impact of OSA on lung cancer.

Sleep apnea is regarded as an important risk factor in the pathogenesis of Alzheimer disease (AD). Chronic intermittent hypoxia treatment (IHT) given during the sleep period of the circadian cycle in experimental animals is a well-established sleep apnea model. Here we report that transient IHT for 4 days on AD model mice causes Aβ overproduction 2 months after IHT presumably via upregulation of synaptic BACE1, side-by-side with tau hyperphosphorylation. These results suggest that even transient IHT may be sufficient to cause long-lasting changes in the molecules measured as AD biomarkers in the brain.

Background: Obstructive sleep apnea (OSA), characterized by chronic intermittent hypoxia (CIH), is a prevalent condition that has been associated with various forms of cancer. Although some clinical studies suggest a potential link between OSA and lung cancer, this association remains uncertain, and the underlying mechanisms are not fully understood. This study investigated the role of the catecholamine-β-adrenergic receptor (βAR) and the NLRP3 inflammasome in mediating the effects of CIH on lung cancer progression in mice. Methods: Male C57BL/6 N mice were subjected to CIH for four weeks, with Lewis lung carcinoma cells seeded subcutaneously. Propranolol (a βAR blocker) or nepicastat (an inhibitor of catecholamine production) was administered during this period. Tumor volume and tail artery blood pressure were monitored. Immunohistochemical staining and immunofluorescence staining were employed to assess protein expression of Ki-67, CD31, VEGFR2, PD-1, PD-L1, and ASC specks in tumor tissues. ELISA was used to detect catecholamine and various cytokines, while western blot assessed the expression of cyclin D1, caspase-1, and IL-1β. In vitro tube formation assay investigated angiogenesis. NLRP3 knockout mice were used to determine the mechanism of NLRP3 in CIH. Results: CIH led to an increase in catecholamine. Catecholamine-βAR inhibitor drugs prevented the increase in blood pressure caused by CIH. Notably, the drugs inhibited CIH-induced murine lung tumor growth, and the expression of Ki-67, cyclin D1, CD31, VEGFR2, PD-1 and PD-L1 in tumor decreased. In vitro, propranolol inhibits tube formation induced by CIH mouse serum. Moreover, CIH led to an increase in TNF-α, IL-6, IL-1β, IFN-γ and sPD-L1 levels and a decrease in IL-10 in peripheral blood, accompanied by activation of NLRP3 inflammasomes in tumor, but these effects were also stopped by drugs. In NLRP3-knockout mice, CIH-induced upregulation of PD-1/PD-L1 in tumor was inhibited. Conclusions: Our study underscores the significant contribution of β-adrenergic signaling and the NLRP3 inflammasome to CIH-induced lung cancer progression. These pathways represent potential therapeutic targets for mitigating the impact of OSA on lung cancer. [ABSTRACT FROM AUTHOR]

Objective: To discuss the alleviative effect of ginsenoside Rg1 on chronic intermittent hypoxia (CIH)-induced brain injury in the mice, and to clarify its possible mechanism. Methods: Forty male C57BL/6 mice were randomly divided into control group, model group, inhibitor group (treated with calpain-1 inhibitor), low dose of ginsenoside Rg1 group (treated with 10 mg·kg-1 ginsenoside Rg1), and high dose of ginsenoside Rg1 group (treated with 20 mg·kg-1 ginsenoside Rg1). Except for the control group, the mice in all other groups were placed in a hypoxic chamber with automatically regulated oxygen concentration to induce hypoxic brain injury. The peripheral blood oxygen saturation (SpO2) of tail of the mice in various groups was detected; the escape latencies and path lengths and the frequency of swimming route crossing the target quadrant of the mice in various groups were determined by Morris water maze test; the levels of blood urea nitrogen (BUN), lactate (LA), malondialdehyde (MDA), interleukin-6 (IL-6), and tumor necrosis factor- α (TNF- α) and the activities of superoxide dismutase (SOD) and lactate dehydrogenase (LDH) in serum of the mice in various groups were detected by kits; the degrees of brain tissue injury of the mice in various groups were observed by HE staining. The levels of reactive oxygen species (ROS) in CA1 region of hippocampus tissue of the mice in various groups were detected by dihydroethidium (DHE) probe; the expression levels of calpain-1, IL-6, and TNF- α proteins in brain tissue of the mice in various groups were detected by Western blotting method. Results: Compared with control group, the SpO2 of the mice in model group was significantly decreased (P<0. 01), indicating that the model was successfully established. Compared with model group, the SpO2 of the mice in inhibitor group, low dose of ginsenoside Rg1 group and high dose of ginsenoside Rg1 group were significantly increased (P<0. 01). The Morris water maze test results showed that compared with control group, the escape latency and path length of the mice in model group were significantly prolonged (P<0. 01), and the frequency of swimming route of crossing the target quadrant was significantly decreased; compared with model group, the escape latencies and path lengths of the mice in inhibitor group, low dose of ginsenoside Rg1 group and high dose of ginsenoside Rg1 group were significantly shortened (P<0. 01), and the frequency of swimming route of crossing the target quadrant was significantly increased. Compared with control group, the levels of BUN, LA, MDA, IL-6, and TNF-α in serum of the mice in model group were significantly increased (P<0. 01), while the activity of LDH was significantly increased (P<0. 01), and the activity of SOD was significantly decreased (P<0. 01); compared with model group, the levels of BUN, LA, MDA, IL-6, and TNF-α in serum of the mice in inhibitor group, low dose of ginsenoside Rg1 group and high dose of ginsenoside Rg1 group were significantly decreased (P<0. 01), while the activities of LDH were significantly decreased (P<0. 01), and the activities of SOD were significantly increased (P<0. 01). The HE staining results showed that compared with control group, the pyramidal neurons in CA1 region of hippocampus tissue of the mice in model group were loosely arranged, while some neurons were triangular, with nuclear pyknosis, cytoplasmic hyperchromasia, and a few neurons were lost, indicating obvious hypoxic neuronal injury; compared with model group, the hypoxic neuronal injury in CA1 region in hippocampus tissue of the mice in inhibitor group, low dose of ginsenoside Rg1 group and high dose of ginsenoside Rg1 group was effectively alleviated. The DHE probe detection showed that compared with control group, the level of ROS in CA1 region in hippocampus tissue of the mice in model group was significantly increased (P<0. 01); compared with model group, the levels of ROS in CA1 region in hippocampus tissue of the mice in inhibitor group, low dose of ginsenoside Rg1 group and high dose of ginsenoside Rg1 group were significantly decreased (P<0. 01). The Western blotting results showed that compared with control group, the expression levels of calpain-1, TNF-α, and IL-6 proteins in hippocampus tissue of the mice in model group were significantly increased (P<0. 01); compared with model group, the expression levels of calpain-1, TNF- α, and IL-6 proteins in hippocampus tissue of the mice in inhibitor group, low dose of GRg1 group and high dose of GRg1 group were significantly decreased (P<0. 01). Conclusion: Ginsenoside Rg1 can alleviate brain tissue injury of the mice induced by CIH; its mechanism may be related to the inhibition of brain tissue inflammatory response and oxidative stress, and the downregulation of calpain-1 expression. [ABSTRACT FROM AUTHOR]

Chronic intermittent hypoxia (CIH) can lead to vascular dysfunction and increase the risk of cardiovascular diseases, cerebrovascular diseases, and arterial diseases. Nevertheless, mechanisms underlying CIH-induced vascular dysfunction remain unclear. Herein, this study analyzed the role of aortic smooth muscle calciumactivated potassium (BK) channels in CIH-induced vascular dysfunction. CIH models were established in rats and rat aortic smooth muscle cells (RASMCs). Hemodynamic parameters such as mean blood pressure (MBP), diastolic blood pressure (DBP), and systolic blood pressure (SBP) were measured in rats, along with an assessment of vascular tone. NO and ET-1 levels were detected in rat serum, and the levels of ET-1, NO, eNOS, p-eNOS, oxidative stress markers (ROS and MDA), and inflammatory factors (IL-6 and TNF-α) were tested in aortic tissues. The Ca2+ concentration in RASMCs was investigated. The activity of BK channels (BKα and BKβ) was evaluated in aortic tissues and RASMCs. SBP, DBP, and MBP were elevated in CIH-treated rats, along with endothelial dysfunction, cellular edema and partial detachment of endothelial cells. BK channel activity was decreased in CIH-treated rats and RASMCs. BK channel activation increased eNOS, p-eNOS, and NO levels while lowering ET-1, ROS, MDA, IL-6, and TNF-α levels in CIH-treated rats. Ca2+ concentration increased in RASMCs following CIH modeling, which was reversed by BK channel activation. BK channel inhibitor (Iberiotoxin) exacerbated CIH-induced vascular disorders and endothelial dysfunction. BK channel activation promoted vasorelaxation while suppressing vascular endothelial dysfunction, inflammation, and oxidative stress, thereby indirectly improving CIH-induced vascular dysfunction. [ABSTRACT FROM AUTHOR]

Background: Chronic intermittent hypoxia (CIH) is the primary cause of myocardial inflammation in obstructive sleep apnea-hypopnea syndrome (OSAHS). Pyroptosis is a newly discovered form of programmed cell death accompanying inflammatory reactions. Our previous study showed that TRPC5 is upregulated in the myocardial injury of CIH rats. The present study aimed to explore the role of TRPC5 in CIH-induced myocardial cell pyroptosis. Methods: A model of CIH in OSA rats was established. SD rats were randomly divided into control group(8rats) and OSA group(8rats). Scanning electron microscope(SEM) was performed on left ventricular tissues slides. Western blot were used to detect the expression levels of pyroptosis-related factors and TRPC5 and its downstream proteins in myocardia tissue. Results: The pyroptosis of myocardial cells by SEM revealed damaged cell membrane integrity of OSA group rats, with fibrous tissue attached to the cell membrane surface, and vesicular protrusions and pyroptotic bodies were observed. Compared to the control group, the expression of pyroptosis-related proteins, such as caspase1, pro-IL-1β, IL-1β, IL-18, GSDMD, and GSDMD-N was upregulated in the OSA group (p < 0.05). Compared to the control group, the expression of TRPC5, NLPR3, p-CaMKIIβ + δ+γ, and HDAC4 was higher in the OSA group (p < 0.05). Conclusions: These findings indicated that the pyroptosis response increases in CIH-induced myocardial injury, and the mechanism that TRPC5 is upregulated, promoting the expression of NLRP3 and inflammasome formation through CaMKII phosphorylation and HDAC4 cytoplasmic translocation. This might be a potential target for the treatment of OSA-induced myocardial injury. [ABSTRACT FROM AUTHOR]

Simple Summary: The incidence of obstructive sleep apnea in children is increasing year by year, and its occurrence and related metabolic and endocrine lesions may be related to hypothalamic dysfunction. Lysine acetylation is a common post-translational modification that is essential for metabolism. The aim of this study was to determine the effects of chronic intermittent hypoxia-induced lysine acetylation on hypothalamic function in an infant mice model, simulating pediatric obstructive sleep apnoea patients. Our study revealed the lysine acetylome and proteomic profile of the hypothalamus induced by chronic intermittent hypoxia in juvenile mice. Differentially acetylated proteins were involved in endocrine metabolism, the citrate cycle (TCA cycle), synapse function, and circadian entrainment. Our findings suggest that chronic intermittent hypoxia may induce metabolic and endocrine dysregulation through modulation of hypothalamic lysine acetylation. Paediatric obstructive sleep apnoea (OSA) is a highly prevalent sleep disorder resulting in chronic intermittent hypoxia (CIH) that has been linked to metabolism and endocrine impairment. Protein acetylation, which is a frequently occurring posttranslational modification, plays pivotal roles in the regulation of hypothalamic processes. However, the effects of CIH-induced global protein acetylation on hypothalamic function and endocrine metabolism remain poorly understood. To bridge this knowledge gap, we conducted a study utilizing liquid chromatography–mass spectrometry to analyse the lysine acetylome and proteome of the hypothalamus in healthy infantile mice exposed to 3 weeks of intermittent hypoxia (as a CIH model) compared to normoxic mice (as controls). Our analysis identified and quantified 2699 Kac sites in 2453 proteins. These acetylated proteins exhibited disruptions primarily in endocrine metabolism, the citrate cycle (TCA cycle), synapse function, and circadian entrainment. Additionally, we observed significant down-regulation of proteins that are known to be involved in endocrine hormone secretion. This study aimed to elucidate the molecular mechanisms underlying CIH-induced alterations in protein acetylation within the hypothalamus. By providing valuable insights into the pathophysiological processes associated with CIH and their impacts on hypothalamic function, our findings contribute to a deeper understanding of the consequences stemming from CIH-induced changes in protein acetylation within the hypothalamus as well as its potential role in endocrine impairment. [ABSTRACT FROM AUTHOR]

Sleep apnea is regarded as an important risk factor in the pathogenesis of Alzheimer disease (AD). Chronic intermittent hypoxia treatment (IHT) given during the sleep period of the circadian cycle in experimental animals is a well-established sleep apnea model. Here we report that transient IHT for 4 days on AD model mice causes Aβ overproduction 2 months after IHT presumably via upregulation of synaptic BACE1, side-by-side with tau hyperphosphorylation. These results suggest that even transient IHT may be sufficient to cause long-lasting changes in the molecules measured as AD biomarkers in the brain. • Sleep apnea is a risk factor in the pathogenesis of Alzheimer disease (AD). • Chronic intermittent hypoxia treatment (IHT) is a model for sleep apnea. • Transient IHT on AD model mice results in long-term Aβ overproduction. • Transient IHT causes upregulation of synaptic BACE1and tau hyperphosphorylation. [ABSTRACT FROM AUTHOR]

Objective: To discuss the effect of the small ubiquitin-like modifier-specific protease 1 (SENP-1)/hypoxia-inducible factor 1α(HIF-1α) pathway on chronic intermittent hypoxia (CIH)-induced vascular endothelial injury in the rats, and to clarify the related mechanism. Methods: The SD rats were randomly divided into control group and CIH group, and then the rats in each group were further divided into 2, 4, and 6-week subgroups, and there were 8 rats in each subgroup. The rats in CIH group were exposed to CIH in a CIH chamber to induce CIH and create the obstructive sleep apnea hypopnea syndrome (OSAHS) models, while the rats in control group were exposed to normoxic conditions. The serum and thoracic aorta tissue of the rats in various groups were collected at each time point. HE staining was used to observe the thoracic aorta vascular injury of the rats in various groups; ELISA method was used to detect the levels of nitric oxide (NO), endothelin-1(ET-1), von Willebrand factor (vWF), and thrombomodulin (TM) in serum of the rats in various groups; Western blotting method was used to detect the expression levels of SENP-1, HIF-1α, and vascular endothelial growth factor A (VEGFA) proteins in thoracic aorta tissue of the rats in various groups. In vitro, the aortic endothelial cells (rAECs) of the rats were cultured and infected with SENP-1 shRNA adenovirus (sh-SENP-1) to construct the cell line with low expression of SENP-1. The CIH was used to induce the vascular endothelial cell injury, and the cells were divided into CIH group, CIH+sh-NC group, and CIH+sh-SENP-1 group; control group was set up separately. CCK-8 method was used to detect the proliferation activities of the cells in various groups; ELISA method was used to detect the activities of lactate dehydrogenase (LDH) in the supernatant and the levels of NO, ET-1, malondialdehyde (MDA), and activities of superoxide dismutase (SOD) in the cells in various groups; flow cytometry was used to detect the apoptotic rates of the cells in various groups; Western blotting method was used to detect the expression levels of SENP-1, HIF-1α, and VEGFA proteins in the cells in various groups. Results: With the extension of CIH induction time, compared with control group, the thoracic aorta endothelium in CIH group gradually became rough and significantly thickened, the level of serum NO of the rats in CIH group was decreased (P<0. 05), and the levels of serum ET-1, vWF, and TM, and the expression levels of SENP-1, HIF-1α, and VEGFA proteins in thoracic aorta tissue were increased (P<0. 05). Compared with control group, the proliferation activity of the cells in CIH group was decreased (P<0. 05), the LDH activity in the supernatant, the levels of ET-1, MDA, and the apoptotic rate in the cells were increased (P<0. 05), while the levels of NO and activity of SOD in the cells were decreased (P<0. 05), and the expression levels of SENP-1, HIF-1α, and VEGFA proteins in the cells were increased (P<0. 05). Compared with CIH group, the proliferation activity of cells in CIH+sh-SENP-1 group was increased (P<0. 05), the activity of LDH in the supernatant, the levels of ET-1, MDA, and the apoptotic rate of the cells were decreased (P<0. 05), while the level of NO and activity of SOD in the cells were increased (P<0. 05), and the expression levels of SENP-1, HIF-1α, and VEGFA proteins were decreased (P<0. 05). Conclusion: The SENP-1/HIF-1α pathway is highly activated in the thoracic aorta injury tissue of the rats induced by CIH. Silencing SENP-1 expression can reduce CIH-induced vascular endothelial cell injury, and its mechanism may be related to downregulating the activation level of SENP-1/HIF-1α pathway. [ABSTRACT FROM AUTHOR]

Pediatric obstructive sleep apnea poses a significant health risk, with potential long‐term consequences on cardiovascular health. This study explores the dichotomous nature of neonatal cardiac response to chronic intermittent hypoxia (CIH) between males and females, aiming to fill a critical knowledge gap in the understanding of sex‐specific cardiovascular consequences of sleep apnea in early life. Neonates were exposed to CIH until p28 and underwent comprehensive in vivo physiological assessments, including whole‐body plethysmography, treadmill stress‐tests, and echocardiography. Results indicated that male CIH rats weighed 13.7% less than age‐matched control males (p = 0.0365), while females exhibited a mild yet significant increased respiratory drive during sleep (93.94 ± 0.84 vs. 95.31 ± 0.81;p = 0.02). Transcriptomic analysis of left ventricular tissue revealed a substantial sex‐based difference in the cardiac response to CIH, with males demonstrating a more pronounced alteration in gene expression compared to females (5986 vs. 3174 genes). The dysregulated miRNAs in males target metabolic genes, potentially predisposing the heart to altered metabolism and substrate utilization. Furthermore, CIH in males was associated with thinner left ventricular walls and dysregulation of genes involved in the cardiac action potential, possibly predisposing males to CIH‐related arrhythmia. These findings emphasize the importance of considering sex‐specific responses in understanding the cardiovascular implications of pediatric sleep apnea. [ABSTRACT FROM AUTHOR]

Obstructive sleep apnea (OSA) is a sleep disorder characterized by intermittent complete or partial occlusion of the airway. Despite a recognized association between OSA and glaucoma, the nature of the underlying link remains unclear. In this study, we investigated whether mild OSA induces morphological, inflammatory, and metabolic changes in the retina resembling those seen in glaucoma using a rat model of OSA known as chronic intermittent hypoxia (CIH). Rats were randomly assigned to either normoxic or CIH groups. The CIH group was exposed to periodic hypoxia during its sleep phase with oxygen reduction from 21% to 10% and reoxygenation in 6 min cycles over 8 h/day. The eyes were subsequently enucleated, and then the retinas were evaluated for retinal ganglion cell number, oxidative stress, inflammatory markers, metabolic changes, and hypoxic response modulation using immunohistochemistry, multiplex assays, and capillary electrophoresis. Statistically significant differences were observed between normoxic and CIH groups for oxidative stress and inflammation, with CIH resulting in increased HIF-1α protein levels, higher oxidative stress marker 8-OHdG, and increased TNF-α. Pyruvate dehydrogenase kinase-1 protein was significantly reduced with CIH. No significant differences were found in retinal ganglion cell number. Our findings suggest that CIH induces oxidative stress, inflammation, and upregulation of HIF-1α in the retina, akin to early-stage glaucoma. [ABSTRACT FROM AUTHOR]

Abstract Background Obstructive sleep apnea (OSA) affects 10–26% of adults in the United States with known sex differences in prevalence and severity. OSA is characterized by elevated inflammation, oxidative stress (OS), and cognitive dysfunction. However, there is a paucity of data regarding the role of sex in the OSA phenotype. Prior findings suggest women exhibit different OSA phenotypes than men, which could result in under-reported OSA prevalence in women. To examine the relationship between OSA and sex, we used chronic intermittent hypoxia (CIH) to model OSA in rats. We hypothesized that CIH would produce sex-dependent phenotypes of inflammation, OS, and cognitive dysfunction, and these sex differences would be dependent on mitochondrial oxidative stress (mtOS). Methods Adult male and female Sprague Dawley rats were exposed to CIH or normoxia for 14 days to examine the impact of sex on CIH-associated circulating inflammation (IL-1β, IL-6, IL-10, TNF-α), circulating steroid hormones, circulating OS, and behavior (recollective and spatial memory; gross and fine motor function; anxiety-like behaviors; and compulsive behaviors). Rats were implanted with osmotic minipumps containing either a mitochondria-targeting antioxidant (MitoTEMPOL) or saline vehicle 1 week prior to CIH initiation to examine how inhibiting mtOS would affect the CIH phenotype. Results Sex-specific differences in CIH-induced inflammation, OS, motor function, and compulsive behavior were observed. In female rats, CIH increased inflammation (plasma IL-6 and IL-6/IL-10 ratio) and impaired fine motor function. Conversely, CIH elevated circulating OS and compulsivity in males. These sex-dependent effects of CIH were blocked by inhibiting mtOS. Interestingly, CIH impaired recollective memory in both sexes but these effects were not mediated by mtOS. No effects of CIH were observed on spatial memory, gross motor function, or anxiety-like behavior, regardless of sex. Conclusions Our results indicate that the impact of CIH is dependent on sex, such as an inflammatory response and OS response in females and males, respectively, that are mediated by mtOS. Interestingly, there was no effect of sex or mtOS in CIH-induced impairment of recollective memory. These results indicate that mtOS is involved in the sex differences observed in CIH, but a different mechanism underlies CIH-induced memory impairments.

Jia Chen,1– 4,&ast; Xiaoyu Deng,1– 4,&ast; Ting Lin,1– 4 Jiefeng Huang,1– 4 Yisong Yang,1– 4 Ningfang Lian1– 4 1Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, People’s Republic of China; 2Fujian Provincial Sleep-Disordered Breathing Clinic Center, Fuzhou, Fujian, People’s Republic of China; 3Institute of Respiratory Disease, Fujian Medical University, Fuzhou, Fujian, People’s Republic of China; 4Department of Respiratory and Critical Care Medicine, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, People’s Republic of China&ast;These two authors contributed equally to this workCorrespondence: Ningfang Lian, Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Fujian Medical University, No. 20, Chazhong Road, Taijiang District, Fuzhou, Fujian Province, 350005, People’s Republic of China, Tel +86-591-87981698, Email 1533532863@qq.comPurpose: Chronic intermittent hypoxia (CIH) related arterial endothelium injury is a common cause of cardiovascular system injury. However, the mechanism still needs to be clarified. In this study, we aimed to clarify the role and mechanism of ferrostatin-1 (Fer-1) in CIH-related rat arterial endothelial cells (ROAEC) ferroptosis.Methods: ROAEC was divided into control group, CIH group, and CIH+ Fer-1 group. Cell viability was detected by cell counting kit 8 kits (CCK8). The apoptotic rate, reactive oxygen species (ROS) levels, Fe2+ levels, and lipid ROS levels were detected by flow cytometry. Malondialdehyde (MDA) levels and nicotinamide adenine dinucleotide (NAD+)/NADH ratio were detected via Elisa kits. The mRNA and protein levels of cystine/glutamate antiporter solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) were detected by qRT-PCR and Western blot. Mitochondrial structure and function were observed by transmission electron microscope (TEM) and mitochondrial membrane potential (MMP). Central carbon metabolism was measured to compare metabolites among each group.Results: After the CIH exposure, ROAEC cell viability decreased; The levels of cell apoptosis, ROS, Fe2+, MDA, and lip ROS increased; The levels of NAD+/NADP ratio decreased; The mRNA and protein levels of GPX4 and SLC7A11 decreased (all p< 0.05). Co-cultured with Fer-1 reversed the levels of apoptosis rate, cell viability, ROS, Fe2+, MAD, lipid ROS, NAD+/NADH ratio and the mRNA and protein expression of GPX4 and SLC7A11 (all p< 0.05). The TEM results showed that damaged mitochondrial membrane and the matrix spillover in the CIH group. The results of the JC-1 assay showed decreased MMP in the CIH group. Fer-1 treatment ameliorated the mitochondrial injury. The results of central carbon metabolism found that CIH altered the metabolites in the TCA cycle, which were reversed by Fer-1 treatment.Conclusion: CIH-induced ferroptosis in ROAEC, which were reversed by Fer-1 via reprogramming mitochondrial function.Keywords: obstructive sleep apnea, chronic intermittent hypoxia, arterial endothelium injury, ferroptosis, mitochondrial function

Obstructive sleep apnea (OSA) can lead to intestinal injury, endotoxemia, and disturbance of intestinal flora. Additionally, as a crucial component of the endocannabinoid system, some studies have demonstrated that cannabinoid 1 (CB1) receptors are closely linked to the multiple organ dysfunction triggered by OSA. However, the role of the CB1 receptor in alleviating OSA-induced colon injury remains unclear. Here, through the construction of the OSA classic model, we found that the colon tissue of chronic intermittent hypoxia (CIH)–induced mice exhibited an overexpression of the CB1 receptor. The results of hematoxylin-eosin staining and transmission electron microscopy revealed that inhibition of the CB1 receptor could decrease the gap between the mucosa and muscularis mucosae, alleviate mitochondrial swelling, reduce microvilli shedding, and promote the recovery of tight junctions of CIH-induced mice. Furthermore, CB1 receptor inhibition reduced the levels of metabolic endotoxemia and inflammatory responses, exhibiting significant protective effects on the colon injury caused by CIH. At the molecular level, through western blotting and real-time polymerase chain reaction techniques, we found that inhibiting the CB1 receptor can significantly increase the expression of ZO-1 and Occludin proteins, which are closely related to the maintenance of intestinal mucosal barrier function. Through 16S rRNA high-throughput sequencing and short-chain fatty acid (SCFA) determination, we found that inhibition of the CB1 receptor increased the diversity of the microbial flora and controlled the makeup of intestinal flora. Moreover, butyric acid concentration and the amount of SCFA-producing bacteria, such as Ruminococcaceae and Lachnospiraceae, were both markedly elevated by CB1 receptor inhibition. The results of the spearman correlation study indicated that Lachnospiraceae showed a positive association with both ZO-1 and Occludin but was negatively correlated with the colon CB1 receptor, IL-1β, and TNF-α. According to this study, we found that inhibiting CB1 receptor can improve CIH-induced colon injury by regulating gut microbiota, reducing mucosal damage and promoting tight junction recovery. Key points: •CIH leads to overexpression of CB1 receptor in colon tissue. •CIH causes intestinal flora disorder, intestinal mucosal damage, and disruption of tight junctions. •Inhibition of CB1 receptor can alleviate the colon injury caused by CIH through regulating the gut microbiota, reducing mucosal injury, and promoting tight junction recovery. [ABSTRACT FROM AUTHOR]

Chronic intermittent hypoxia (CIH) is associated with an increased risk of cardiovascular diseases. Previously, we have shown that berberine (BBR) is a potential cardioprotective agent. However, its effect and mechanism on CIH‐induced cardiomyopathy remain uncovered. This study was designed to determine the effects of BBR against CIH‐induced cardiac damage and to explore the molecular mechanisms. Mice were exposed to 5 weeks of CIH with or without the treatment of BBR and adeno‐associated virus 9 (AAV9) carrying SIRT6 or SIRT6‐specific short hairpin RNA. The effect of BBR was evaluated by echocardiography, histological analysis and western blot analysis. CIH caused the inactivation of myocardial SIRT6 and AMPK‐FOXO3a signalling. BBR dose‐dependently ameliorated cardiac injury in CIH‐induced mice, as evidenced by increased cardiac function and decreased fibrosis. Notably, SIRT6 overexpression mimicked these beneficial effects, whereas infection with recombinant AAV9 carrying SIRT6‐specific short hairpin RNA abrogated them. Mechanistically, BBR reduced oxidative stress damage and preserved mitochondrial function via activating SIRT6‐AMPK‐FOXO3a signalling, enhancing mitochondrial biogenesis as well as PINK1‐Parkin‐mediated mitophagy. Taken together, these data demonstrate that SIRT6 activation protects against the pathogenesis of CIH‐induced cardiac dysfunction. BBR attenuates CIH‐induced myocardial injury by improving mitochondrial biogenesis and PINK1‐Parkin‐dependent mitophagy via the SIRT6‐AMPK‐FOXO3a signalling pathway. [ABSTRACT FROM AUTHOR]

Chronic intermittent hypoxia (CIH) is a prevalent condition characterized by recurrent episodes of oxygen deprivation, linked to respiratory and neurological disorders. Prolonged CIH is known to have adverse effects, including endothelial dysfunction, chronic inflammation, oxidative stress, and impaired neuronal function. These factors can contribute to serious comorbidities, including metabolic disorders and cardiovascular diseases. To investigate the molecular impact of CIH, we examined male C57BL/6J mice exposed to CIH for 21 days, comparing with normoxic controls. We used single-nucleus RNA sequencing to comprehensively examine the transcriptomic impact of CIH on key cell classes within the brainstem, specifically excitatory neurons, inhibitory neurons, and oligodendrocytes. These cell classes regulate essential physiological functions, including autonomic tone, cardiovascular control, and respiration. Through analysis of 10,995 nuclei isolated from pontine-medullary tissue, we identified seven major cell classes, further subdivided into 24 clusters. Our findings among these cell classes, revealed significant differential gene expression, underscoring their distinct responses to CIH. Notably, neurons exhibited transcriptional dysregulation of genes associated with synaptic transmission, and structural remodeling. In addition, we found dysregulated genes encoding ion channels and inflammatory response. Concurrently, oligodendrocytes exhibited dysregulated genes associated with oxidative phosphorylation and oxidative stress. Utilizing CellChat network analysis, we uncovered CIH-dependent altered patterns of diffusible intercellular signaling. These insights offer a comprehensive transcriptomic cellular atlas of the pons-medulla and provide a fundamental resource for the analysis of molecular adaptations triggered by CIH. NEW & NOTEWORTHY This study on chronic intermittent hypoxia (CIH) from pons-medulla provides initial insights into the molecular effects on excitatory neurons, inhibitory neurons, and oligodendrocytes, highlighting our unbiased approach, in comparison with earlier studies focusing on single target genes. Our findings reveal that CIH affects cell classes distinctly, and the dysregulated genes in distinct cell classes are associated with synaptic transmission, ion channels, inflammation, oxidative stress, and intercellular signaling, advancing our understanding of CIH-induced molecular responses. [ABSTRACT FROM AUTHOR]

Purpose: Obstructive sleep apnea (OSA) is highly comorbid with Alzheimer's disease (AD) and may represent a risk factor for inducing or accelerating cognitive impairment in AD. Chronic intermittent hypoxia (CIH) has been considered to be a predictor of developing cognitive decline and AD. However, the precise underlying mechanisms by which CIH contributes to cognitive impairment remain unknown. In the present study, we examined the effects of CIH on cognition and hippocampal function in APP/PS1 mice, an animal model of AD. Methods: Wild-type (WT) and APP/PS1 mice were subjected to one of the following conditions for 2 weeks: (1) sham condition (continuous room air) or (2) CIH condition. The oxygen concentration of the CIH condition transitioned from 5 to 21%. Behavioral tests, electrophysiological recording, real-time polymerase chain reaction, and Western blot were used to assess the effect of CIH on cognitive performance and synaptic plasticity. Results: CIH exposure did not affect motor coordination, general locomotor activity, anxiety, or willingness to explore. However, behavioral test results indicated that APP/PS1-CIH mice showed more spatial learning and memory deficits. CIH induced long-term potentiation (LTP) dysfunction of the hippocampus in WT mice. These effects were aggravated in APP/PS1 mice. The N-methyl-D-aspartic acid receptor (NMDAR) NR1 subunit and postsynaptic density 95 (PSD95) in the hippocampus of WT and APP/PS1 mice were downregulated. Conclusions: These findings showed that a postsynaptic mechanism was involved in the effect of CIH on cognitive impairment. [ABSTRACT FROM AUTHOR]

The sympathetic nervous system modulates arterial blood pressure. Individuals with obstructive sleep apnea (OSA) experience numerous nightly hypoxic episodes and exhibit elevated sympathetic activity to the cardiovascular system leading to hypertension. This suggests that OSA disrupts normal respiratorysympathetic coupling. This study investigates the role of the postinspiratory complex (PiCo) and preBötzinger complex (preBötC) in respiratory-sympathetic coupling under control conditions and following exposure to chronic intermittent hypoxia (CIH) for 21 days (5% O2-80 bouts/day). The surface of the ventral brainstem was exposed in urethane (1.5 g/kg) anesthetized, spontaneously breathing adult mice. Cholinergic (ChAT), glutamatergic (Vglut2), and neurons that co-express ChAT and Vglut2 at PiCo, as well as Dbx1 and Vglut2 neurons at preBötC, were optogenetically stimulated while recording activity from the diaphragm (DIA), vagus nerve (cVN), and cervical sympathetic nerve (cSN). Following CIH exposure, baseline cSN activity increased, breathing frequency increased, and expiratory time decreased. In control mice, stimulating PiCo specific cholinergic-glutamatergic neurons caused a sympathetic burst during all phases of the respiratory cycle, whereas optogenetic activation of cholinergicglutamatergic PiCo neurons in CIH mice increased sympathetic activity only during postinspiration and late expiration. Stimulation of glutamatergic PiCo neurons increased cSN activity during the postinspiratory phase in control and CIH mice. Optogenetic stimulation of ChAT containing neurons in the PiCo area did not affect sympathetic activity under control or CIH conditions. Stimulating Dbx1 or Vglut2 neurons in preBötC evoked an inspiration and a concomitant cSN burst under control and CIH conditions. Taken together, these results suggest that PiCo and preBötC contribute to respiratory-sympathetic coupling, which is altered by CIH, and may contribute to the hypertension observed in patients with OSA. [ABSTRACT FROM AUTHOR]

Chronic intermittent hypoxia (CIH), a principal pathophysiological aspect of obstructive sleep apnea (OSA), is associated with cognitive deficits. Clinical evidence suggests that a combination of Shengmaisan and Liuwei Dihuang Decoctions (SMS-LD) can enhance cognitive function by nourishing yin and strengthening the kidneys. This study aimed to assess the efficacy and underlying mechanisms of SMS-LD in addressing cognitive impairments induced by CIH. We exposed C57BL/6N mice to CIH for five weeks (20%−5% O 2 , 5 min/cycle, 8 h/day) and administered SMS-LD intragastrically (15.0 or 30 g·kg−1·day) 30 min before each CIH session. Additionally, AG490, a JJanus kinase 2 (JAK2) inhibitor, was administered via intracerebroventricular injection. Cognitive function was evaluated using the Morris water maze, while synaptic and mitochondrial structures were examined by transmission electron microscopy. Oxidative stress levels were determined using DHE staining, and the activation of the erythropoietin (ER)/ER receptor (EPOR)/JAK2 signaling pathway was analyzed through immunohistochemistry and Western blotting. To further investigate molecular mechanisms, HT22 cells were treated in vitro with either SMS-LD medicated serum alone or in combination with AG490 and then exposed to CIH for 48 h. Our results indicate that SMS-LD significantly mitigated CIH-induced cognitive impairments in mice. Specifically, SMS-LD treatment enhanced dendritic spine density, ameliorated mitochondrial dysfunction, reduced oxidative stress, and activated the EPO/EPOR/JAK2 signaling pathway. Conversely, AG490 negated SMS-LD's neuroprotective and cognitive improvement effects under CIH conditions. These findings suggest that SMS-LD's beneficial impact on cognitive impairment and synaptic and mitochondrial integrity under CIH conditions may predominantly be attributed to the activation of the EPO/EPOR/JAK2 signaling pathway. [ABSTRACT FROM AUTHOR]

Conditions associated with chronic hypoxia increase morbidity and mortality attributable to cardiovascular complications. Myocardial hypoxia is a common feature in several diseases including: stroke, infarction, anaemia, chronic lung diseases, obstructive sleep apnoea and cyanotic congenital heart defects. The present study was planned to investigate the cardiovascular effects of chronic intermittent hypoxia and its association with increased myocardial oxidative stress. In addition, to evaluate the protective effect of chromium supplementation, aiming at achieving an alternative that may enable to devise a therapy for hypoxic patients. Male rats were allocated into three groups: control group (normoxic), untreated hypoxic group (exposed to hypoxia 8 h/day, 5 days/week for 6 weeks) and hypoxic group supplemented with chromium picolinate (90 µg/kg/day by gavage). Rats were subjected to measurement of body weight, haematocrit value, mean arterial blood pressure, heart rate and ECG recording. Cardiac activities of isolated hearts were studied on Langendorff preparation under basal conditions and in response to ischaemia/reperfusion. Thereafter, cardiac weights were determined and cardiac tissue catalase activity as well as malondialdhyde level were assessed. Significant results were obtained upon exposure to hypoxia including; low body weight, increased haematocrit, elevated blood pressure, left ventricular hypertrophy and impaired cardiac activities, basally and in response to ischaemia/reperfusion challenges, associated with increased oxidative stress in cardiac tissue. At the same time, chromium supplementation increased body weight, lowered blood pressure, reduced ventricular hypertrophy and significantly improved the cardiac performance. Chromium supplementation confers protection against hypoxia-induced cardiovascular dysfunction by improvement of the antioxidant capacity. [ABSTRACT FROM AUTHOR]

Background: Obstructive sleep apnea (OSA) affects 10–26% of adults in the United States with known sex differences in prevalence and severity. OSA is characterized by elevated inflammation, oxidative stress (OS), and cognitive dysfunction. However, there is a paucity of data regarding the role of sex in the OSA phenotype. Prior findings suggest women exhibit different OSA phenotypes than men, which could result in under-reported OSA prevalence in women. To examine the relationship between OSA and sex, we used chronic intermittent hypoxia (CIH) to model OSA in rats. We hypothesized that CIH would produce sex-dependent phenotypes of inflammation, OS, and cognitive dysfunction, and these sex differences would be dependent on mitochondrial oxidative stress (mtOS). Methods: Adult male and female Sprague Dawley rats were exposed to CIH or normoxia for 14 days to examine the impact of sex on CIH-associated circulating inflammation (IL-1β, IL-6, IL-10, TNF-α), circulating steroid hormones, circulating OS, and behavior (recollective and spatial memory; gross and fine motor function; anxiety-like behaviors; and compulsive behaviors). Rats were implanted with osmotic minipumps containing either a mitochondria-targeting antioxidant (MitoTEMPOL) or saline vehicle 1 week prior to CIH initiation to examine how inhibiting mtOS would affect the CIH phenotype. Results: Sex-specific differences in CIH-induced inflammation, OS, motor function, and compulsive behavior were observed. In female rats, CIH increased inflammation (plasma IL-6 and IL-6/IL-10 ratio) and impaired fine motor function. Conversely, CIH elevated circulating OS and compulsivity in males. These sex-dependent effects of CIH were blocked by inhibiting mtOS. Interestingly, CIH impaired recollective memory in both sexes but these effects were not mediated by mtOS. No effects of CIH were observed on spatial memory, gross motor function, or anxiety-like behavior, regardless of sex. Conclusions: Our results indicate that the impact of CIH is dependent on sex, such as an inflammatory response and OS response in females and males, respectively, that are mediated by mtOS. Interestingly, there was no effect of sex or mtOS in CIH-induced impairment of recollective memory. These results indicate that mtOS is involved in the sex differences observed in CIH, but a different mechanism underlies CIH-induced memory impairments. Highlights: This is the first study to examine the contribution of sex on CIH-induced inflammation, steroid hormones, oxidative stress, and behavioral dysfunction in rats. CIH increased circulating inflammation and fine motor dysfunction in females, whereas CIH increased circulating oxidative stress and compulsivity in males. Inhibition of mitochondrial oxidative stress blocked sex-specific effects of CIH in males and females. CIH induced recollective memory impairments in males and females, which was not prevented by blocking mitochondrial oxidative stress. Plain language summary: Sleep apnea is a common sleeping condition in adults with a wide range of symptoms that include inflammation, oxidative stress, memory problems, anxiety, and compulsivity. Men are diagnosed with sleep apnea more often than women. Although there is limited information on how sleep apnea affects men and women differently, previous studies suggest that women may exhibit different sleep apnea symptoms than men. To examine the impact of male and female sex on common sleep apnea symptoms, we exposed adult male and female rats to a model of sleep apnea called chronic intermittent hypoxia (CIH). We found that many effects of CIH were different in males and females. CIH females had increased inflammation and motor problems, whereas CIH males had increased oxidative stress and compulsivity. To investigate the reason for these CIH sex differences, we blocked mitochondrial oxidative stress. Blocking mitochondrial oxidative stress decreased CIH associated sex differences. However, blocking mitochondrial oxidative stress had no impact on CIH-induced memory impairment that was observed in male and female rats. Our findings support previous reports that suggest that women exhibit different sleep apnea symptoms than men. Further, we extend these findings by showing that mitochondrial oxidative stress is involved in these sex differences. Clinically, patients diagnosed with sleep apnea are typically treated with continuous positive airway pressure (CPAP) machines, which have high rates of non-compliance (15–40%). Therefore, understanding why sleep apnea is causing these symptoms will be important in developing therapeutics. [ABSTRACT FROM AUTHOR]

Abstract Pediatric obstructive sleep apnea poses a significant health risk, with potential long‐term consequences on cardiovascular health. This study explores the dichotomous nature of neonatal cardiac response to chronic intermittent hypoxia (CIH) between males and females, aiming to fill a critical knowledge gap in the understanding of sex‐specific cardiovascular consequences of sleep apnea in early life. Neonates were exposed to CIH until p28 and underwent comprehensive in vivo physiological assessments, including whole‐body plethysmography, treadmill stress‐tests, and echocardiography. Results indicated that male CIH rats weighed 13.7% less than age‐matched control males (p = 0.0365), while females exhibited a mild yet significant increased respiratory drive during sleep (93.94 ± 0.84 vs. 95.31 ± 0.81;p = 0.02). Transcriptomic analysis of left ventricular tissue revealed a substantial sex‐based difference in the cardiac response to CIH, with males demonstrating a more pronounced alteration in gene expression compared to females (5986 vs. 3174 genes). The dysregulated miRNAs in males target metabolic genes, potentially predisposing the heart to altered metabolism and substrate utilization. Furthermore, CIH in males was associated with thinner left ventricular walls and dysregulation of genes involved in the cardiac action potential, possibly predisposing males to CIH‐related arrhythmia. These findings emphasize the importance of considering sex‐specific responses in understanding the cardiovascular implications of pediatric sleep apnea.

Objective To investigate the role of triggering receptor expressed on myeloid cells-1(TREM-1) in atherosclerosis induced by chronic intermittent hypoxia (CIH). Methods ApoE-/- mice were randomly divided into blank group, model group and experimental group. The mice in the model group and the experimental group were kept in a hypoxic environment and fed with a high-fat diet. After 4 weeks of high-fat feeding, mice in the experimental group were intraperitoneally injected with TREM-1 inhibitor LR12 (5 mg/kg) for 8 weeks. After 12 weeks of feeding, the level of serum total cholesterol (TC), low density lipoprotein (LDL), triglyceride (TG), tumor necrosis factor-α (TNF-α), interleukin-1β(IL-1β) and interleukin-10 (IL-10) were detected. Histological analysis of aortic TREM-1 expression, plaque area and macrophage level were examined. Results Compared with blank group, the expression of TREM-1 in the aorta of the model group significantly increased (P＜0.05). Compared with model group, the aortic plaque, the level of lipids in serum(TC, LDL, TG) and inflammatory factors (TNF-α, IL-1β, IL-10), aortic plaque, the expression of TREM-1 and infiltrating macrophages in aortic plaque of the experimental group were all significantly reduced (P＜0.05). Conclusions TREM-1 is involved in the development of CIH-induced AS. Inhibition of TREM-1 can alleviate CIH-induced AS and its mechanism is related to the inhibition of macrophage activation.

Abstract Background Obstructive sleep apnea (OSA) is associated with increased risk of lung cancer mortality. Nevertheless, little is known about the underlying molecular mechanisms. This research aimed to investigate differentially expressed genes (DEGs) and explore their function in Lewis lung carcinoma (LLC)-bearing mice exposed to chronic intermittent hypoxia (CIH) by transcriptome sequencing. Methods Lung cancer tissues in LLC-bearing mice exposed to CIH or normoxia were subjected for transcriptome sequencing to examine DEGs. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses were employed to explore the function of DEGs. To evaluate the prognostic value of DEGs, the Kaplan–Meier survival analysis in combination with Cox proportional hazard model were applied based on The Cancer Genome Atlas. Results A total of 388 genes with 207 up-regulated and 181 down-regulated genes were differentially expressed between the CIH and normoxia control groups. Bioinformatics analysis revealed that the DEGs were related to various signaling pathways such as chemokine signaling pathway, IL-17 signaling pathway, TGF-β signaling pathway, transcriptional misregulation in cancer, natural killer cell mediated cytotoxicity, PPAR signaling pathway. In addition, the DEGs including APOL1, ETFB, KLK8, PPP1R3G, PRL, SPTA1, PLA2G3, PCP4L1, NINJ2, MIR186, and KLRG1 were proven to be significantly correlated with poorer overall survival in lung adenocarcinoma. Conclusions CIH caused a significant change of gene expression profiling in LLC-bearing mice. The DEGs were found to be involved in various physiological and pathological processes and correlated with poorer prognosis in lung cancer.

Obstructive sleep apnea (OSA) is a common respiratory disorder, primarily characterized by two pathological features: chronic intermittent hypoxia (CIH) and sleep deprivation (SD). OSA has been identified as a risk factor for numerous diseases, and the inflammatory response related to programmed cell necrosis is believed to play a significant role in the occurrence and progression of multisystem damage induced by OSA, with increasing attention being paid to pyroptosis. Recent studies have indicated that OSA can elevate oxidative stress levels in the body, activating the process of pyroptosis within different tissues, ultimately accelerating organ dysfunction. However, the molecular mechanisms of pyroptosis in the multisystem damage induced by OSA remain unclear. Therefore, this review focuses on four major systems that have received concentrated attention in existing research in order to explore the role of pyroptosis in promoting renal diseases, cardiovascular diseases, neurocognitive diseases, and skin diseases in OSA patients. Furthermore, we provide a comprehensive overview of methods for inhibiting pyroptosis at different molecular levels, with the goal of identifying viable targets and therapeutic strategies for addressing OSA-related complications.

Objective To investigate the role of triggering receptor expressed on myeloid cells-1(TREM-1) in atherosclerosis induced by chronic intermittent hypoxia (CIH). Methods ApoE-/- mice were randomly divided into blank group, model group and experimental group. The mice in the model group and the experimental group were kept in a hypoxic environment and fed with a high-fat diet. After 4 weeks of high-fat feeding, mice in the experimental group were intraperitoneally injected with TREM-1 inhibitor LR12 (5 mg/kg) for 8 weeks. After 12 weeks of feeding, the level of serum total cholesterol (TC), low density lipoprotein (LDL), triglyceride (TG), tumor necrosis factor-α (TNF-α), interleukin-1β(IL-1β) and interleukin-10 (IL-10) were detected. Histological analysis of aortic TREM-1 expression, plaque area and macrophage level were examined. Results Compared with blank group, the expression of TREM-1 in the aorta of the model group significantly increased (P＜0.05). Compared with model group, the aortic plaque, the level of lipids in serum(TC, LDL, TG) and inflammatory factors (TNF-α, IL-1β, IL-10), aortic plaque, the expression of TREM-1 and infiltrating macrophages in aortic plaque of the experimental group were all significantly reduced (P＜0.05). Conclusions TREM-1 is involved in the development of CIH-induced AS. Inhibition of TREM-1 can alleviate CIH-induced AS and its mechanism is related to the inhibition of macrophage activation. [ABSTRACT FROM AUTHOR]

Introduction: The objective of this study was to examine the potential induction of senescence in vascular endothelial cells (VECs) by chronic intermittent hypoxia (CIH), a defining characteristic of obstructive sleep apnea (OSA). This investigation seeks to elucidate the underlying mechanisms that contribute to the development of cardiovascular diseases in patients with OSA, with a particular focus on CIH-induced vascular aging. Methods: The BioSpherix-OxyCycler system was used to establish models of CIH in both rats and human umbilical vein endothelial cells (HUVECs). To assess VECs' senescence, various methods were employed including EdU incorporation assay, cell cycle analysis, senescence-associated β-galactosidase (SA-β-gal) staining, and senescence protein testing. Vascular aging was evaluated through measurements of carotid-femoral pulse wave velocity, intima-media thickness, and Ki67 immunohistochemical staining. In order to identify the molecular mechanisms associated with CIH-induced senescence in VECs, a bioinformatics study was conducted utilizing the Gene Expression Omnibus database. Results: Under conditions of CIH, HUVECs exhibited inhibited proliferation, arrested cell cycle, increased activity of SA-β-gal, and elevated expression levels of p53 and p21 compared to HUVECs under normoxic conditions. Similarly, rats exposed to CIH displayed increased carotid-femoral pulse wave velocity, intima-media thickness, vascular permeability, and SA-β-gal activity in VECs, along with decreased expression of arterial Ki67. BTG3-associated protein (BANP) was found to be highly expressed in CIH-induced VECs. Furthermore, the overexpression of BANP resulted in the senescence of VECs, along with elevated levels of p53 phosphorylation and nuclear localization. Conclusions: These findings demonstrate that CIH can induce VECs senescence and contribute to vascular aging. Additionally, BANP can induce VECs senescence by promoting p53 phosphorylation and nuclear retention. These discoveries offer novel insights into the increased cardiovascular risk associated with OSA, thereby presenting new possibilities for therapeutic intervention. [ABSTRACT FROM AUTHOR]

Purpose: This study evaluated the effects of chronic intermittent hypoxia (CIH) at different times on the mitochondria of mouse hearts and H9C2 cardiomyocytes to determine the role of the cannabinoid receptor 1 (CB1R)/adenosine 5'-monophosphate–activated protein kinase (AMPK)/peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) signaling pathway. Methods: Animal and cellular CIH models were prepared in an intermittent hypoxia chamber at different times. The cardiac function of mice was determined, and heart tissue and ultrastructural changes were observed. Apoptosis, reactive oxygen species (ROS), and mitochondrial membrane potential were detected, and MitoTracker™ staining was performed to observe cardiomyocyte mitochondria. Western blot, immunohistochemistry, and cellular immunofluorescence were also performed. Results: In the short-term CIH group, increases in mouse ejection fraction (EF) and heart rate (HR); mitochondrial division; ROS and mitochondrial membrane potential; and the expression levels of CB1R, AMPK, and PGC-1α were observed in vivo and in vitro. In the long-term CIH group, the EF and HR increased, the myocardial injury and mitochondrial damage were more severe, mitochondrial synthesis decreased, the apoptosis percentage and ROS increased, mitochondrial fragmentation increased, membrane potential decreased, CB1R expression increased, and AMPK and PGC-1α expression levels decreased. Targeted blocking of CB1R can increase AMPK and PGC-1α, reduce damage attributed to long-term CIH in mouse hearts and H9C2 cells, and promote mitochondrial synthesis. Conclusion: Short-term CIH can directly activate the AMPK/PGC-1α pathway, promote mitochondrial synthesis in cardiomyocytes, and protect cardiac structure and function. Long-term CIH can increase CB1R expression and inhibit the AMPK/PGC-1α pathway, resulting in structural damage, the disturbance of myocardial mitochondria synthesis, and further alterations in the cardiac structure. After targeted blocking of CB1R, levels of AMPK and PGC-1α increased, alleviating damage to the heart and cardiomyocytes caused by long-term CIH. [ABSTRACT FROM AUTHOR]

• NLRP3 inflammasome inhibition improves CIH-induced cognitive impairment in mice. • CIH activates microglia-specific NLRP3 inflammasome via ROS-NF-κB signaling. • IL-1β releases from microglia in a GSDMD-dependent manner without pyroptosis. • IL-1β impairs cognitive function by impairing synaptic plasticity of hippocampus. Hypoxia/reoxygenation caused by chronic intermittent hypoxia (CIH) plays an important role in cognitive deficits in patients with obstructive sleep apnea. However, the precise underlying mechanism remains unclear. This study investigated whether the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is involved in CIH-induced spatial learning and memory impairment in mice, and the possible underlying upstream and downstream mechanisms. The C57BL/6 male mice were exposed to CIH (21% O 2 -6% O 2 , 4 min/cycle, 8 h/day) for 9 weeks to investigate the role of NLRP3 in CIH-induced spatial learning and memory impairment in mice. BV2 cells were exposed to intermittent hypoxia (21% O 2 -1% O 2 , 90 min/cycle) for 48 h to investigate the possible mechanisms in vitro. We found that: 1) inhibition of NLRP3 inflammasome activation improved CIH-induced spatial learning and memory impairment in mice. 2) CIH damaged hippocampal neurons but increased the number of microglia in mice hippocampi; CIH activated microglia-specific NLRP3 inflammasome, leading to upregulation of matured IL-1β and N-GSDMD. 3) intermittent hypoxia activated NLRP3 inflammasome via the ROS-NF-κB signaling pathway to promote the release of matured IL-1β from microglia in a GSDMD-dependent manner without pyroptosis. 4) The IL-1β released from microglia might impair the synaptic plasticity of hippocampal CA3-CA1 synapses by acting on IL-1 receptors in hippocampal neurons. Our findings reveal that ROS-NF-κB-NLRP3 inflammasome-GSDMD dependent IL-1β release from microglia may participate in CIH-induced spatial learning and memory impairment by acting on hippocampal neuronal IL-1 receptor, leading to synaptic plasticity impairment. [ABSTRACT FROM AUTHOR]

Aim: Chronic intermittent hypoxia (CIH) is a key characteristic of obstructive sleep apnea (OSA) syndrome, a chronic respiratory disorder. The mechanisms of CIH-induced metabolic disturbance and histopathological damage remain unclear. Methods: CIH-induced rats underwent daily 8-h CIH, characterized by oxygen levels decreasing from 21% to 8.5% over 4 min, remaining for 2 min, and quickly returning to 21% for 1 min. The control rats received a continuous 21% oxygen supply. The levels of hypersensitive C reactive protein (h-CRP), tumor necrosis factor-a (TNF-a), interleukin 6 (IL-6), interleukin 8 (IL-8), and nuclear factor kappa-B (NF-kB) were measured by ELISA. Histological analysis of the soft palates was conducted using HE staining. The microbial profiling of fecal samples was carried out by Accu16STM assay. Untargeted metabolomics of serum and soft palate tissue samples were analyzed by UPLC-MS. The protein expression of cAMP-related pathways in the soft palate was determined by Western blot. Results: After 28 h of CIH induction, a significant increase in pro-inflammatory cytokines was observed in the serum, along with mucosal layer thickening and soft palate tissue hypertrophy. CIH induction altered the diversity and composition of fecal microbiota, specifically reducing beneficial bacteria while increasing harmful bacteria/opportunistic pathogens. Notably, CIH induction led to a significant enrichment of genera such as Dorea, Oscillibacter, Enteractinococcus, Paenibacillus, Globicatella, and Flaviflexus genera. Meanwhile, Additionally, CIH induction had a notable impact on 108 serum marker metabolites. These marker metabolites, primarily involving amino acids, organic acids, and a limited number of flavonoids or sterols, were associated with protein transport, digestion and absorption, amino acid synthesis and metabolism, as well as cancer development. Furthermore, these differential serum metabolites significantly affected 175 differential metabolites in soft palate tissue, mainly related to cancer development, signaling pathways, amino acid metabolism, nucleotide precursor or intermediate metabolism, respiratory processes, and disease. Importantly, CIH induction could significantly affect the expression of the cAMP pathway in soft palate tissue. Conclusions: Our findings suggest that targeting differential metabolites in serum and soft palate tissue may represent a new approach to clinical intervention and treatment of OSA simulated by the CIH. [ABSTRACT FROM AUTHOR]

Chronic intermittent hypoxia (CIH, a model for sleep apnoea) is a major risk factor for several cardiovascular diseases. Autonomic imbalance (sympathetic overactivity and parasympathetic withdrawal) has emerged as a causal contributor of CIH‐induced cardiovascular disease. Previously, we showed that CIH remodels the parasympathetic pathway. However, whether CIH induces remodelling of the cardiac sympathetic innervation remains unknown. Mice (male, C57BL/6J, 2–3 months) were exposed to either room air (RA, 21% O2) or CIH (alternating 21% and 5.7% O2, every 6 min, 10 h day–1) for 8–10 weeks. Flat‐mounts of their left and right atria were immunohistochemically labelled for tyrosine hydroxylase (TH, a sympathetic marker). Using a confocal microscope (or fluorescence microscope) and Neurlocudia 360 digitization and tracing system, we scanned both the left and right atria and quantitatively analysed the sympathetic axon density in both groups. The segmentation data was mapped onto a 3D mouse heart scaffold. Our findings indicated that CIH significantly remodelled the TH immunoreactive (‐IR) innervation of the atria by increasing its density at the sinoatrial node, the auricles and the major veins attached to the atria (P < 0.05, n = 7). Additionally, CIH increased the branching points of TH‐IR axons and decreased the distance between varicosities. Abnormal patterns of TH‐IR axons around intrinsic cardiac ganglia were also found following CIH. We postulate that the increased sympathetic innervation may further amplify the effects of enhanced CIH‐induced central sympathetic drive to the heart. Our work provides an anatomical foundation for the understanding of CIH‐induced autonomic imbalance. Key points: Chronic intermittent hypoxia (CIH, a model for sleep apnoea) causes sympathetic overactivity, cardiovascular remodelling and hypertension.We determined the effect of CIH on sympathetic innervation of the mouse atria.In vivo CIH for 8–10 weeks resulted in an aberrant axonal pattern around the principal neurons within intrinsic cardiac ganglia and an increase in the density, branching point, tortuosity of catecholaminergic axons and atrial wall thickness.Utilizing mapping tool available from NIH (SPARC) Program, the topographical distribution of the catecholaminergic innervation of the atria were integrated into a novel 3D heart scaffold for precise anatomical distribution and holistic quantitative comparison between normal and CIH mice.This work provides a unique neuroanatomical understanding of the pathophysiology of CIH‐induced autonomic remodelling. [ABSTRACT FROM AUTHOR]

Objective: To explore the changes in levels of angiogenic T lymphocyte (Tang)in the peripheral blood of rats exposed to chronic intermittent hypoxia (CIH)during early atherosclerotic vascular changes. Methods: Healthy adult Sprague Dawley (SD)rats were randomly divided into two groups: the normal feeding group (RA group)and the chronic intermittent hypoxia group (IH group), with the IH exposed to intermittent hypoxia for 8 h per day for a total of 6 weeks. The intermittent hypoxia pattern was set to repeat every 2 min, with 40 s of nitrogen gas to reduce the oxygen concentration from 21% to 8% and stabilize for 20 s, followed by normal air to restore the oxygen concentration to 21% for 40 s and maintain for 20 s. After modeling, levels of Tang and endothelial progenitor cells (EPC)were measured by flow cytometry. Levels of high⁃density lipoprotein cholesterol (HDL⁃C), low⁃density lipoprotein cholesterol (LDL ⁃C), triglycerides (TG), total cholesterol (TC), and homocysteine (Hcy)were measured by ELISA. pathological changes were observed in HE stained pathological sections of the thoracic aorta. Results: Flow cytometry results showed that compared to the RA group, the levels of Tang in rats of the IH group were significantly elevated [ (22.975±1.866)% vs. (15.713±1.746)%, P < 0.001], and there was no statistical difference in EPC levels [ (0.040±0.028)% vs. (0.028±0.012)%, P > 0.05]；H E staining results showed that the IMT of rats thoracic aorta in the IH group was significantly increased compared to the RA group [ (121.275 ± 30.896)μm vs. (84.075±7.452)μm, P < 0.05]；ELISA results showed that the Hcy level in the IH group was significantly higher compared to the RA group [ (6.2±0.6)μmol/L vs (. 5.5±0.6)μmol/L, P < 0.05], but there were no statistical differences in HDL ⁃C, LDL ⁃C, TC, and TG levels. Conclusion: Early atherosclerosis occurs in the blood vessels of CIH rats and the levels of Tang elevated, suggesting that the level of Tang is related to the occurrence and development of early atherosclerosis. [ABSTRACT FROM AUTHOR]

Perinatal hypoxia is an inadequate delivery of oxygen to the fetus in the period immediately before, during, or after the birth process. The most frequent form of hypoxia occurring in human development is chronic intermittent hypoxia (CIH) due to sleep-disordered breathing (apnea) or bradycardia events. CIH incidence is particularly high with premature infants. During CIH, repetitive cycles of hypoxia and reoxygenation initiate oxidative stress and inflammatory cascades in the brain. A dense microvascular network of arterioles, capillaries, and venules is required to support the constant metabolic demands of the adult brain. The development and refinement of this microvasculature is orchestrated throughout gestation and in the initial weeks after birth, at a critical juncture when CIH can occur. There is little knowledge on how CIH affects the development of the cerebrovasculature. However, since CIH (and its treatments) can cause profound abnormalities in tissue oxygen content and neural activity, there is reason to believe that it can induce lasting abnormalities in vascular structure and function at the microvascular level contributing to neurodevelopmental disorders. This mini-review discusses the hypothesis that CIH induces a positive feedback loop to perpetuate metabolic insufficiency through derailment of normal cerebrovascular development, leading to long-term deficiencies in cerebrovascular function. [ABSTRACT FROM AUTHOR]

The sympathetic nervous system modulates arterial blood pressure. Individuals with obstructive sleep apnea (OSA) experience numerous nightly hypoxic episodes and exhibit elevated sympathetic activity to the cardiovascular system leading to hypertension. This suggests that OSA disrupts normal respiratory-sympathetic coupling. This study investigates the role of the postinspiratory complex (PiCo) and preBötzinger complex (preBötC) in respiratory-sympathetic coupling under control conditions and following exposure to chronic intermittent hypoxia (CIH) for 21 days (5% O2–80 bouts/day). The surface of the ventral brainstem was exposed in urethane (1.5 g/kg) anesthetized, spontaneously breathing adult mice. Cholinergic (ChAT), glutamatergic (Vglut2), and neurons that co-express ChAT and Vglut2 at PiCo, as well as Dbx1 and Vglut2 neurons at preBötC, were optogenetically stimulated while recording activity from the diaphragm (DIA), vagus nerve (cVN), and cervical sympathetic nerve (cSN). Following CIH exposure, baseline cSN activity increased, breathing frequency increased, and expiratory time decreased. In control mice, stimulating PiCo specific cholinergic-glutamatergic neurons caused a sympathetic burst during all phases of the respiratory cycle, whereas optogenetic activation of cholinergic-glutamatergic PiCo neurons in CIH mice increased sympathetic activity only during postinspiration and late expiration. Stimulation of glutamatergic PiCo neurons increased cSN activity during the postinspiratory phase in control and CIH mice. Optogenetic stimulation of ChAT containing neurons in the PiCo area did not affect sympathetic activity under control or CIH conditions. Stimulating Dbx1 or Vglut2 neurons in preBötC evoked an inspiration and a concomitant cSN burst under control and CIH conditions. Taken together, these results suggest that PiCo and preBötC contribute to respiratory-sympathetic coupling, which is altered by CIH, and may contribute to the hypertension observed in patients with OSA.

The present study aimed to investigate the impact of hydrogen (H2) on chronic intermittent hypoxia (CIH)-induced cardiac hypertrophy in mice by modulating iron metabolism. C57BL/6N mice were randomly allocated into four groups: control (Con), CIH, CIH + H2, and H2. The mice were exposed to CIH (21–5% FiO2, 3 min/cycle, 8 h/d), and received inhalation of a hydrogen–oxygen mixture (2 h/d) for 5 weeks. Cardiac and mitochondrial function, levels of reactive oxygen species (ROS), and iron levels were evaluated. The H9C2 cell line was subjected to intermittent hypoxia (IH) and treated with H2. Firstly, we found H2 had a notable impact on cardiac hypertrophy, ameliorated pathological alterations and mitochondrial morphology induced by CIH (p < 0.05). Secondly, H2 exhibited a suppressive effect on oxidative injury by decreasing levels of inducible nitric oxide synthase (i-NOS) (p < 0.05) and 4-hydroxynonenal (4-HNE) (p < 0.01). Thirdly, H2 demonstrated a significant reduction in iron levels within myocardial cells through the upregulation of ferroportin 1 (FPN1) proteins (p < 0.01) and the downregulation of transferrin receptor 1 (TfR1), divalent metal transporter 1 with iron-responsive element (DMT1(+ire)), and ferritin light chain (FTL) mRNA or proteins (p < 0.05). Simultaneously, H2 exhibited the ability to decrease the levels of Fe2+ and ROS in H9C2 cells exposed to IH (p < 0.05). Moreover, H2 mediated the expression of hepcidin, hypoxia-inducible factor-1α (HIF-1α) (p < 0.01), and iron regulatory proteins (IRPs), which might be involved in the regulation of iron-related transporter proteins. These results suggested that H2 may be beneficial in preventing cardiac hypertrophy, a condition associated with reduced iron toxicity.

Abstract Background Gestational sleep apnea is a hypoxic sleep disorder that affects 8–26% of pregnancies and increases the risk for central nervous system dysfunction in offspring. Specifically, there are sex differences in the sensitivity of the fetal hippocampus to hypoxic insults, and hippocampal impairments are associated with social dysfunction, repetitive behaviors, anxiety, and cognitive impairment. Yet, it is unclear whether gestational sleep apnea impacts these hippocampal-associated functions and if sex and age modify these effects. To examine the relationship between gestational sleep apnea and hippocampal-associated behaviors, we used chronic intermittent hypoxia (CIH) to model late gestational sleep apnea in pregnant rats. We hypothesized that late gestational CIH would produce sex- and age-specific social, anxiety-like, repetitive, and cognitive impairments in offspring. Methods Timed pregnant Long-Evans rats were exposed to CIH or room air normoxia from GD 15–19. Behavioral testing of offspring occurred during either puberty or young adulthood. To examine gestational hypoxia-induced behavioral phenotypes, we quantified hippocampal-associated behaviors (social function, repetitive behaviors, anxiety-like behaviors, and spatial memory and learning), hippocampal neuronal activity (glutamatergic NMDA receptors, dopamine transporter, monoamine oxidase-A, early growth response protein 1, and doublecortin), and circulating hormones in offspring. Results Late gestational CIH induced sex- and age-specific differences in social, repetitive, and memory functions in offspring. In female pubertal offspring, CIH impaired social function, increased repetitive behaviors, and elevated circulating corticosterone levels but did not impact memory. In contrast, CIH transiently induced spatial memory dysfunction in pubertal male offspring but did not impact social or repetitive functions. Long-term effects of gestational CIH on social behaviors were only observed in female offspring, wherein CIH induced social disengagement and suppression of circulating corticosterone levels in young adulthood. No effects of gestational CIH were observed in anxiety-like behaviors, hippocampal neuronal activity, or circulating testosterone and estradiol levels, regardless of sex or age of offspring. Conclusions Our results indicate that hypoxia-associated pregnancy complications during late gestation can increase the risk for behavioral and physiological outcomes in offspring, such as social dysfunction, repetitive behaviors, and cognitive impairment, that are dependent on sex and age.

Paediatric obstructive sleep apnoea (OSA) is a highly prevalent sleep disorder resulting in chronic intermittent hypoxia (CIH) that has been linked to metabolism and endocrine impairment. Protein acetylation, which is a frequently occurring posttranslational modification, plays pivotal roles in the regulation of hypothalamic processes. However, the effects of CIH-induced global protein acetylation on hypothalamic function and endocrine metabolism remain poorly understood. To bridge this knowledge gap, we conducted a study utilizing liquid chromatography–mass spectrometry to analyse the lysine acetylome and proteome of the hypothalamus in healthy infantile mice exposed to 3 weeks of intermittent hypoxia (as a CIH model) compared to normoxic mice (as controls). Our analysis identified and quantified 2699 Kac sites in 2453 proteins. These acetylated proteins exhibited disruptions primarily in endocrine metabolism, the citrate cycle (TCA cycle), synapse function, and circadian entrainment. Additionally, we observed significant down-regulation of proteins that are known to be involved in endocrine hormone secretion. This study aimed to elucidate the molecular mechanisms underlying CIH-induced alterations in protein acetylation within the hypothalamus. By providing valuable insights into the pathophysiological processes associated with CIH and their impacts on hypothalamic function, our findings contribute to a deeper understanding of the consequences stemming from CIH-induced changes in protein acetylation within the hypothalamus as well as its potential role in endocrine impairment.

Obstructive sleep apnea (OSA) is a sleep disorder characterized by intermittent complete or partial occlusion of the airway. Despite a recognized association between OSA and glaucoma, the nature of the underlying link remains unclear. In this study, we investigated whether mild OSA induces morphological, inflammatory, and metabolic changes in the retina resembling those seen in glaucoma using a rat model of OSA known as chronic intermittent hypoxia (CIH). Rats were randomly assigned to either normoxic or CIH groups. The CIH group was exposed to periodic hypoxia during its sleep phase with oxygen reduction from 21% to 10% and reoxygenation in 6 min cycles over 8 h/day. The eyes were subsequently enucleated, and then the retinas were evaluated for retinal ganglion cell number, oxidative stress, inflammatory markers, metabolic changes, and hypoxic response modulation using immunohistochemistry, multiplex assays, and capillary electrophoresis. Statistically significant differences were observed between normoxic and CIH groups for oxidative stress and inflammation, with CIH resulting in increased HIF-1α protein levels, higher oxidative stress marker 8-OHdG, and increased TNF-α. Pyruvate dehydrogenase kinase-1 protein was significantly reduced with CIH. No significant differences were found in retinal ganglion cell number. Our findings suggest that CIH induces oxidative stress, inflammation, and upregulation of HIF-1α in the retina, akin to early-stage glaucoma.