Long-term intermittent hypoxia in mice induces inflammatory pathways implicated in sleep apnea and steatohepatitis in humans.

Obstructive sleep apnea (OSA) induces intermittent hypoxia (IH), an independent risk factor for non-alcoholic fatty liver disease (NAFLD). While the molecular links between IH and NAFLD progression are unclear, immune cell-driven inflammation plays a crucial role in NAFLD pathogenesis. Using lean mice exposed to long-term IH and a cohort of lean OSA patients (n = 71), we conducted comprehensive hepatic transcriptomics, lipidomics, and targeted serum proteomics.

Differential Impact of Intermittent vs. Sustained Hypoxia on HIF-1, VEGF and Proliferation of HepG2 Cells.

Obstructive sleep apnea (OSA) is an emerging risk factor for cancer occurrence and progression, mainly mediated by intermittent hypoxia (IH). Systemic IH, a main landmark of OSA, and local sustained hypoxia (SH), a classical feature at the core of tumors, may act separately or synergistically on tumor cells. Our aim was to compare the respective consequences of intermittent and sustained hypoxia on HIF-1, endothelin-1 and VEGF expression and on cell proliferation and migration in HepG2 liver tumor cells.

Intermittent Hypoxia-Induced Cardiomyocyte Death Is Mediated by HIF-1 Dependent MAM Disruption.

Rationale: Intermittent hypoxia (IH) is one of the main features of sleep-disordered breathing (SDB). Recent findings indicate that hypoxia inducible factor-1 (HIF-1) promotes cardiomyocytes apoptosis during chronic IH, but the mechanisms involved remain to be elucidated. Here, we hypothesize that IH-induced ER stress is associated with mitochondria-associated ER membrane (MAM) alteration and mitochondrial dysfunction, through HIF-1 activation.

Chronic intermittent hypoxia, a hallmark of obstructive sleep apnea, promotes 4T1 breast cancer development through endothelin-1 receptors.

The association between obstructive sleep apnea (OSA) and cancer is still debated and data are scarce regarding the link between OSA and breast cancer progression. Since conclusive epidemiological studies require large sample sizes and sufficient duration of exposure before incident cancer occurrence, basic science studies represent the most promising approach to appropriately address the topic. Here we assessed the impact of intermittent hypoxia (IH), the major hallmark of OSA, on the development of breast cancer and explored the specific involvement of the endothelin signaling pathway.

Intermittent Hypoxia Rewires the Liver Transcriptome and Fires up Fatty Acids Usage for Mitochondrial Respiration.

Sleep Apnea Syndrome (SAS) is one of the most common chronic diseases, affecting nearly one billion people worldwide. The repetitive occurrence of abnormal respiratory events generates cyclical desaturation-reoxygenation sequences known as intermittent hypoxia (IH). Among SAS metabolic sequelae, it has been established by experimental and clinical studies that SAS is an independent risk factor for the development and progression of non-alcoholic fatty liver disease (NAFLD).

Intermittent Hypoxia Triggers Early Cardiac Remodeling and Contractile Dysfunction in the Time-Course of Ischemic Cardiomyopathy in Rats.

BACKGROUND Sleep-disordered breathing is associated with a poor prognosis (mortality) in patients with ischemic cardiomyopathy. The understanding of mechanisms linking intermittent hypoxia (IH), the key feature of sleep-disordered breathing, to ischemic cardiomyopathy progression is crucial for identifying specific actionable therapeutic targets. The aims of the present study were (1) to evaluate the impact of IH on the time course evolution of cardiac remodeling and contractile dysfunction in a rat model of ischemic cardiomyopathy; and (2) to determine the impact of IH on sympathetic activity, hypoxia inducible factor-1 activation, and endoplasmic reticulum stress in the time course of ischemic cardiomyopathy progression.

Curcumin prevents chronic intermittent hypoxia-induced myocardial injury.

Background: Chronic intermittent hypoxia (IH), the hallmark feature of obstructive sleep apnoea syndrome, contributes to infarct size enhancement after myocardial ischemia-reperfusion (I/R). Curcumin (Curc), the natural pigment of , has been demonstrated to be beneficial in the context of myocardial injury. In this study, we assessed the effects of Curc on the maladaptive cardiac response to IH, and particularly on IH-induced hypoxia inducible factor-1 (HIF-1) expression, oxidative stress, inflammation, endoplasmic reticulum (ER) stress and apoptosis.

Cooperation Between Hypoxia-Inducible Factor 1α and Activating Transcription Factor 4 in Sleep Apnea-Mediated Myocardial Injury.

Chronic intermittent hypoxia (CIH) occurring during sleep apnea amplifies infarct size owing to ischemia-reperfusion. CIH activates hypoxia-inducible factor 1 (HIF-1) and activating transcription factor 4 (ATF4). However, whether HIF-1 and ATF4 interact to promote cardiomyocyte death remains unexplored.

Pharmacokinetic study of intravenously administered artemisinin-loaded surface-decorated amphiphilic γ-cyclodextrin nanoparticles.

Artemisinin and its derivatives are currently recommended by World Health Organization for the treatment of malaria. Severe malaria requires a parenteral administration of artemisinin-based formulations. However, the effective use of artemisinin is limited by the pharmacokinetic characteristics of the drug (low water solubility, poor bioavailability and short half-life).

Lebetin 2, a Snake Venom-Derived B-Type Natriuretic Peptide, Provides Immediate and Prolonged Protection against Myocardial Ischemia-Reperfusion Injury via Modulation of Post-Ischemic Inflammatory Response.

Myocardial infarction (MI) followed by left ventricular (LV) remodeling is the most frequent cause of heart failure. Lebetin 2 (L2), a snake venom-derived natriuretic peptide, exerts cardioprotection during acute myocardial ischemia-reperfusion (IR) ex vivo. However, its effects on delayed consequences of IR injury, including post-MI inflammation and fibrosis have not been defined.

Zinc deficiency promotes endothelin secretion and endothelial cell migration through nuclear hypoxia-inducible factor-1 translocation.

Zinc is involved in the expression and function of various transcription factors, including the hypoxia-inducible factor-1 (HIF-1). HIF-1 and its target gene endothelin-1 (ET-1) are activated by intermittent hypoxia (IH), one of the main consequences of obstructive sleep apnea (OSA), and both play a key role in the cardiovascular consequences of IH. Because OSA and IH are associated with zinc deficiency, we investigated the effect of zinc deficiency caused by chelation on the HIF-1/ET-1 pathway and its functional consequences in endothelial cells.

Chronic neuromuscular electrical stimulation improves muscle mass and insulin sensitivity in a mouse model.

Muscle wasting reduces functional capacity and increases cardiometabolic risk in chronic disease. Neuromuscular electrical stimulation (NMES) of the lower limb has been shown to reverse muscle wasting in these patients but its effect on cardiometabolic health is unclear. We investigated a mouse model of in-vivo non-invasive chronic NMES on muscle mass, insulin sensitivity and arterial blood pressure (BP).

Chronic Intermittent Hypoxia Alters Rat Ophthalmic Artery Reactivity Through Oxidative Stress, Endothelin and Endothelium-Derived Hyperpolarizing Pathways.

Purpose: Obstructive sleep apnea recently has been associated with a higher frequency of ischemic optic neuropathies. Intermittent hypoxia (IH) has been proposed as a major component of obstructive sleep apnea cardiovascular consequences. However, there currently are no pathophysiologic data regarding the effect of IH on the ocular vascular system.

Chronic intermittent hypoxia promotes myocardial ischemia-related ventricular arrhythmias and sudden cardiac death.

We investigated the effects of intermittent hypoxia (IH), such as that encountered in severe obstructive sleep apnea (OSA) patients, on the development and severity of myocardial ischemia-related ventricular arrhythmias. Rats were exposed to 14 days of IH (30 s at 5%O and 30 s at 21%O, 8 h·day) or normoxia (N, similar air-air cycles) and submitted to a 30-min coronary ligature. Arterial blood pressure (BP) and ECG were recorded for power spectral analysis, ECG interval measurement and arrhythmia quantification.

Diseases of the retina and the optic nerve associated with obstructive sleep apnea.

Many associations between ocular disorders and obstructive sleep apnea (OSA) have been studied, such as nonarteritic anterior ischemic optic neuropathy, glaucoma, papilledema, retinal vein occlusion, eyelid hyperlaxity, lower-eyelid ectropion and recurrent corneal erosions. The objective of this review is to synthetize the possible vascular disorders of the retina and the optic nerve associated with sleep apnea patients and to discuss the underlying pathophysiological hypotheses. Main mechanisms involved in the ocular complications of OSA are related to intermittent hypoxia, sympathetic system activation, oxidant stress, and deleterious effects of endothelin 1.

Chronic Intermittent Hypoxia Impairs Insulin Sensitivity but Improves Whole-Body Glucose Tolerance by Activating Skeletal Muscle AMPK.

Obstructive sleep apnea syndrome is a highly prevalent disease resulting in transient respiratory arrest and chronic intermittent hypoxia (cIH). cIH is associated with insulin resistance and impaired metabolic homeostasis in rodents and humans, but the exact underlying mechanisms remain unclear. In the current study, we investigated the effects of 2 weeks of cIH (1-min cycle, fraction of inspired oxygen 21-5%, 8 h/day) on whole-body insulin sensitivity and glucose tolerance in lean mice.

An innovative intermittent hypoxia model for cell cultures allowing fast Po oscillations with minimal gas consumption.

Performing hypoxia-reoxygenation cycles in cell culture with a cycle duration accurately reflecting what occurs in obstructive sleep apnea (OSA) patients is a difficult but crucial technical challenge. Our goal was to develop a novel device to expose multiple cell culture dishes to intermittent hypoxia (IH) cycles relevant to OSA with limited gas consumption. With gas flows as low as 200 ml/min, our combination of plate holders with gas-permeable cultureware generates rapid normoxia-hypoxia cycles.

Intermittent hypoxia in obese Zucker rats: cardiometabolic and inflammatory effects.

What is the central question of this study? This study addresses the relative impact of obesity and intermittent hypoxia in the pathophysiological process of obstructive sleep apnoea by investigating the metabolic, inflammatory and cardiovascular consequences of intermittent hypoxia in lean and obese Zucker rats. What is the main finding and its importance? We found that obesity and intermittent hypoxia have mainly distinct consequences on the investigated inflammatory and cardiometabolic parameters in Zucker rats. This suggests that, for a given severity of sleep apnea, the association of obesity and obstructive sleep apnoea may not necessarily be deleterious.

Lebetin 2, a Snake Venom-Derived Natriuretic Peptide, Attenuates Acute Myocardial Ischemic Injury through the Modulation of Mitochondrial Permeability Transition Pore at the Time of Reperfusion.

Cardiac ischemia is one of the leading causes of death worldwide. It is now well established that natriuretic peptides can attenuate the development of irreversible ischemic injury during myocardial infarction. Lebetin 2 (L2) is a new discovered peptide isolated from Macrovipera lebetina venom with structural similarity to B-type natriuretic peptide (BNP).

Targeting the ROS-HIF-1-endothelin axis as a therapeutic approach for the treatment of obstructive sleep apnea-related cardiovascular complications.

Obstructive sleep apnea (OSA) is now recognized as an independent and important risk factor for cardiovascular diseases such as hypertension, coronary heart disease, heart failure and stroke. Clinical and experimental data have confirmed that intermittent hypoxia is a major contributor to these deleterious consequences. The repetitive occurrence of hypoxia-reoxygenation sequences generates significant amounts of free radicals, particularly in moderate to severe OSA patients.

Hypoxia-inducible factor prolyl hydroxylase 1 (PHD1) deficiency promotes hepatic steatosis and liver-specific insulin resistance in mice.

Obesity is associated with local tissue hypoxia and elevated hypoxia-inducible factor 1 alpha (HIF-1α) in metabolic tissues. Prolyl hydroxylases (PHDs) play an important role in regulating HIF-α isoform stability. In the present study, we investigated the consequence of whole-body PHD1 gene (Egln2) inactivation on metabolic homeostasis in mice.