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Cause and effect diagram of obstructive sleep apnea (OSA)-related diseases. Although intermittent hypoxia (IH) in OSA is a known risk factor for diabetes, systematic hypertension, and cardiovascular diseases, the cellular mechanisms underlying the relationship between IH and cardiovascular diseases remain elusive. Despite a large number of studies of IH, the molecular mechanism of IH on vascular smooth muscle cells is less established.

Cause and effect diagram of obstructive sleep apnea (OSA)-related diseases. Although intermittent hypoxia (IH) in OSA is a known risk factor for diabetes, systematic hypertension, and cardiovascular diseases, the cellular mechanisms underlying the relationship between IH and cardiovascular diseases remain elusive. Despite a large number of studies of IH, the molecular mechanism of IH on vascular smooth muscle cells is less established.

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Obstructive sleep apnea (OSA) is characterized by intermittent hypoxia (IH) and is a risk factor for cardiovascular diseases (e.g., atherosclerosis) and chronic inflammatory diseases (CID). The excessive proliferation of vascular smooth muscle cells (VSMCs) plays a pivotal role in the progression of atherosclerosis. Hypoxia-inducible factor-1 and n...

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... is a highly prevalent disorder [3,4]; Peppard et al. estimated that the prevalence of moderate to severe sleep-disordered breathing is 10% and 3% among 30-to 49-year-old men and women, respectively, and 17% and 9% among 50-to 70-year-old men and women, respectively [3]. Furthermore, OSA is well known as a risk factor for diabetes, systematic hypertension, and cardiovascular diseases [5][6][7][8][9][10][11][12][13][14][15][16], and also increases mortality from cardiovascular diseases (Figure 1) [17,18]. ...

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... Further studies have shown that diabetic patients with OSA may increase oxidative stress and damage microcirculation [25] to promote the activation of PARP and reduce the density of nerve fibers in the epidermis [31], thus leading to the occurrence of neuropathy. Intermittent hypoxemia will not only increase reactive oxygen species and oxygen free radicals, activate different cascades, positively regulate inflammatory reactions, cause endothelial cell secretion dysfunction, promote cell apoptosis, destroy vascular endothelial integrity, lead to endothelial dysfunction, and then lead to extensive vascular damage [32], but also promote the excessive proliferation of vascular smooth muscle cells, This leads to the occurrence and development of atherosclerosis [33]. OSA promotes the occurrence and severity of diabetic LEAD. ...
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Diabetic foot is one of the most serious and painful chronic complications of diabetic patients, especially elderly diabetic patients. It has a high rate of death, disability and amputation. Obstructive sleep apnea (OSA) is a treatable chronic sleep disorder. Existing evidence suggests that OSA may promote the development and delay the healing of diabetic foot, and continuous positive airway pressure therapy may promote the healing of ulcers. Therefore, in the multidisciplinary diagnosis and treatment of diabetes, cooperation with sleep medicine should be strengthened, and the basic and clinical research on diabetic foot combined with OSA should be strengthened, so as to reduce the amputation rate, improve the cure rate and reduce the incidence of cardiovascular events.
... In 2019, the Special Issue of the International Journal of Molecular Sciences (IJMS), "Sleep Apnea and Intermittent Hypoxia", covered several aspects of SAS and IH [3][4][5][6][7][8][9][10]. To continue the previous Special Issue, the second volume, "Sleep Apnea and Intermittent Hypoxia 2.0", explores more insights into SAS and IH and collected seven publications that consist of two original research articles and five literature reviews. ...
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Sleep apnea syndrome (SAS) is the most common form of sleep-disordered breathing and is associated with many adverse health consequences, including increased overall mortality risk [...]
... It has been suggested that intermittent hypoxemia during sleep increases oxidative stress, the production of free radicals. This may cause an inflammatory cascade, leading to increased vascular permeability, vasoconstriction, a proliferation of vascular smooth muscle cells, platelet aggregation, thrombosis and the acceleration of atherosclerosis [4,15,16]. Intermittent hypoxia triggers mitochondrial dysfunction, resulting in increased upregulation of nuclear factor kappa B (NF-κB) in neutrophils/monocytes, increasing the production of adhesion molecules, inflammatory cytokines and adipokines [17]. Vascular wall hypoxia promotes the thrombogenic potential of atherosclerotic plaques and thrombus formation via prothrombotic factor upregulation [17]. ...
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Background: Obstructive sleep apnea is associated with an increased prevalence of cardiovascular disease. The mechanism of these associations is not completely understood. We aimed to investigate the association of the apnea hypopnea index and the degree of airflow limitation with endothelial dysfunction. Methods: This was a single-center prospective study of patients admitted for diagnostic coronary angiography (CAG). Endothelial function was assessed by the non-invasive EndoPAT system by reactive hyperemia index (RHI) and divided into two groups: endothelial dysfunction and normal endothelial function. Sleep apnea signs were detected by WatchPAT measuring the respiratory disturbance index (pRDI), the apnea and hypopnea index (pAHI), and the oxygen desaturation index (ODI). Patients underwent spirometry and body plethysmography. Based on CAG, the severity of coronary artery disease was assessed as follows: no significant coronary artery disease, single-, two- and three-vessel disease. Results: A total of 113 patients were included in the study. Breathing disorders measured by WatchPAT and spirometry were more severe in patients with endothelial dysfunction: pRDI (27.3 vs. 14.8, p = 0.001), pAHI (24.6 vs. 10.3, p < 0.001), ODI (13.7 vs. 5.2, p = 0.002), forced expiratory volume in one second (FEV1) (81.2 vs. 89, p = 0.05). In a multivariate regression analysis, pAHI and FEV1 were independent predictors of endothelial dysfunction assessed by RHI. There was no correlation between the severity of coronary artery disease and endothelial dysfunction. Conclusions: Obstructive sleep apnea signs and greater airflow limitation were associated with endothelial dysfunction regardless of the severity of the coronary artery disease.
... The involvement of these pathologies can lead to chronic diseases of multiple organs. A number of conditions may occur including atherosclerosis, cardiovascular disease, cerebrovascular disease, immunodeficiency, and metabolic abnormalities (pancreatic β cell dysfunction, insulin resistance, and increased free-fatty acid [FFA]) may occur [4][5][6][7][8][9][10][11]. ...
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Sleep apnea syndrome (SAS) is a prevalent disorder characterized by recurrent apnea or hypoxia episodes leading to intermittent hypoxia (IH) and arousals during sleep. Currently, the relationship between SAS and metabolic diseases is being actively analyzed, and SAS is considered to be an independent risk factor for the development and progression of insulin resistance/type 2 diabetes (T2DM). Accumulating evidence suggests that the short cycles of decreased oxygen saturation and rapid reoxygenation, a typical feature of SAS, contribute to the development of glucose intolerance and insulin resistance. In addition to IH, several pathological conditions may also contribute to insulin resistance, including sympathetic nervous system hyperactivity, oxidative stress, vascular endothelial dysfunction, and the activation of inflammatory cytokines. However, the detailed mechanism by which IH induces insulin resistance in SAS patients has not been fully revealed. We have previously reported that IH stress may exacerbate insulin resistance/T2DM, especially in hepatocytes, adipocytes, and skeletal muscle cells, by causing abnormal cytokine expression/secretion from each cell. Adipose tissues, skeletal muscle, and the liver are the main endocrine organs producing hepatokines, adipokines, and myokines, respectively. In this review, we focus on the effect of IH on hepatokine, adipokine, and myokine expression.
... For instance, hypoxia suppresses the activity of cyclin-dependent kinase inhibitors through upregulating miRNAs, thus allowing vascular smooth muscles to proliferate [40,41], which may lead to decreased compliance of pulmonary arteries and aggravate right heart failure. In addition, hypoxia acts as a stimulus in mediating inflammation by increasing NF-κB activity, and the expression of various proinflammatory cytokines, particularly IL-6, will be increased [42]. Proinflammatory cytokines, such as IL-6, IL-1β and IL-33, can accelerate the proliferation of vascular smooth muscle cells [43][44][45]. ...
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... The HIF-1α activates the NFκB, a transcription factor which regulates several pro-inflammatory genes, including TNFα, interleukin (IL)-8, and IL-6 [24]. IL-6, the epidermal growth factor family ligands, and tyrosine kinase receptors induced by IH may be involved in the proliferation of vascular smooth muscle cells [25]. Another study showed that a further vascular and cardiac dys-function in mice under IH can be triggered by trombospondin-1 though cardiac fibroblast activation and increasing angiotensin II activity [26]. ...
... The HIF-1α activates the NFκB, a transcription factor which regulates several pro-inflammatory genes, including TNFα, interleukin (IL)-8, and IL-6 [24]. IL-6, the epidermal growth factor family ligands, and tyrosine kinase receptors induced by IH may be involved in the proliferation of vascular smooth muscle cells [25]. Another study showed that a further vascular and cardiac dysfunction in mice under IH can be triggered by trombospondin-1 though cardiac fibroblast activation and increasing angiotensin II activity [26]. ...
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... Two major transcription pathways are responsible for IH-induced intracellular mechanisms: the HIF1 and the NF-κB pathways (reviewed in [71]). IH-mediated activation of HIF1 and NF-κB leads to the synthesis of molecules with effects on inflammation, immune surveillance and cell proliferation, and have been reported in cancer [72], microglia inflammation [73] and atherosclerosis [74]. Related to these findings, we have previously reported that chronic IH exposures during sleep lead to the recruitment of CD36 + high macrophages to the aortic wall and trigger atherogenesis, through epigenetic activation of atherogenic and inflammatory pathways [75]. ...
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Aim: Late-gestational sleep fragmentation (LG-SF) and intermittent hypoxia (LG-IH), two hallmarks of obstructive sleep apnea, lead to metabolic dysfunction in the offspring. We investigated specific biological processes that are epigenetically regulated by LG-SF and LG-IH. Materials & methods: We analyzed DNA methylation profiles in offspring visceral white adipose tissues by MeDIP-chip followed by pathway analysis. Results: We detected 1187 differentially methylated loci (p < 0.01) between LG-SF and LG-IH. Epigenetically regulated genes in LG-SF offspring were associated with lipid and glucose metabolism, whereas those in LG-IH were related to inflammatory signaling and cell proliferation. Conclusion: While LG-SF and LG-IH will result in equivalent phenotypic alterations in offspring, each paradigm appears to operate through epigenetic regulation of different biological processes.
... Besides being produced by macrophages (35), IL-6 is also produced by a variety of different resident cells including keratinocytes, enterocytes, hepatocytes (33), pneumocytes, and bronchial epithelial cell (36), smooth muscle cells (37), skeletal muscle cells (38), osteoblasts (39), adipocytes (40), neurons (35,41). Interestingly IL-6 was also shown to be produced by lung epithelial cells in response to a variety of different stimuli including allergens, respiratory virus and exercise (42)(43)(44). ...
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... IH triggers excessive proliferation of vascular smooth muscle cells, which play important roles in AS progression (36). It is reported that the production of IL-6 induced the upregulation of epiregulin, which contributed to the proliferation of smooth muscle cells (37). ...
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The occurrence and development of atherosclerosis could be influenced by intermittent hypoxia. Obstructive sleep apnea (OSA), characterized by intermittent hypoxia, is world-wide prevalence with increasing morbidity and mortality rates. Researches remain focused on the study of its mechanism and improvement of diagnosis and treatment. However, the underlying mechanism is complex, and the best practice for OSA diagnosis and treatment considering atherosclerosis and related cardiovascular diseases is still debatable. In this review, we provided an update on research in OSA in the last 5 years with regard to atherosclerosis. The processes of inflammation, oxidative stress, autonomic nervous system activation, vascular dysfunction, platelet activation, metabolite dysfunction, small molecule RNA regulation, and the cardioprotective occurrence was discussed. Additionally, improved diagnosis such as, the utilized of portable device, and treatment especially with inconsistent results in continuous positive airway pressure and mandibular advancement devices were illustrated in detail. Therefore, further fundamental and clinical research should be carried out for a better understanding the deep interaction between OSA and atherosclerosis, as well as the suggestion of newer diagnostic and treatment options.
... Moreover, ET-1 triggers NF-κB by HIF-1 in human VSMC caused by persistent hypoxia causing systemic inflammatory remodeling [101]. Hence, in vascular inflammation, NF-κB and HIF-1 have interdependent functions and pathways [102]. ...
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Hypoxia, the decline of tissue oxygen stress, plays a role in mediating cellular processes. Cardiovascular disease, relatively widespread with increased mortality, is closely correlated with oxygen homeostasis regulation. Besides, hypoxia-inducible factor-1(HIF-1) is reported to be a crucial component in regulating systemic hypoxia-induced physiological and pathological modifications like oxidative stress, damage, angiogenesis, vascular remodeling, inflammatory reaction, and metabolic remodeling. In addition, HIF1 controls the movement, proliferation, apoptosis, differentiation and activity of numerous core cells, such as cardiomyocytes, endothelial cells (ECs), smooth muscle cells (SMCs), and macrophages. Here we review the molecular regulation of HIF-1 in cardiovascular diseases, intended to improve therapeutic approaches for clinical diagnoses. Better knowledge of the oxygen balance control and the signal mechanisms involved is important to advance the development of hypoxia-related diseases.