Hospitalized acute exacerbation in chronic obstructive pulmonary disease - impact on long-term renal outcomes.

INTRODUCTION: Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is a common and preventable event in patients with chronic obstructive pulmonary disease (COPD). Data regarding the impact of AECOPD on short- and long-term renal outcomes are lacking. METHODS: We included all COPD patients who were followed at Queen Mary Hospital (QMH) in year 2015 and reviewed their clinical/renal outcomes in subsequent five years. Relationships between AECOPD and adverse renal outcomes were evaluated. RESULTS: 371 COPD patients were included. 169 patients had hospitalized AECOPD in past one year (HAE group) while 202 patients did not (non-HAE group). 285 patients (76.8%) had renal progression/death and 102 (27.5%) patients developed acute kidney injury (AKI). HAE group showed a more rapid eGFR decline than non-HAE group (-4.64 mL/min/1.73m2/year vs. -2.40 mL/min/1.73m2/year, p = 0.025). HAE group had significantly higher risk for renal progression/death at 5 years [adjusted OR (aOR) 2.380 (95% CI = 1.144-4.954), p = 0.020]. The frequency of hospitalized AECOPD in past 3 years, any AECOPD in past 3 years, hospitalized AECOPD in past 3 years were also predictive of renal progression/death at 5 years [aOR were 1.176 (95% CI = 1.038- 1.331), 2.998 (95% CI = 1.438-6.250) and 2.887 (95% CI = 1.409-5.917) respectively; p = 0.011, 0.003 and 0.004]. HAE group also showed significantly higher risk of AKI [adjusted HR (aHR) 2.430; 95% CI = 1.306-4.519, p = 0.005]. CONCLUSIONS: AECOPD, in particular HAE, was associated with increased risk of renal progression/death and AKI. Prevention of AECOPD, especially HAE, may potentially improve short- and long-term renal outcomes in COPD patients.

Strategies to Assess the Effect of Continuous Positive Airway Pressure on Long-Term Clinically Important Outcomes among Patients with Symptomatic Obstructive Sleep Apnea: An Official American Thoracic Society Workshop Report.

Continuous positive airway pressure (CPAP) is the first-line treatment for obstructive sleep apnea (OSA). Although CPAP improves symptoms (e.g., daytime sleepiness), there is a lack of high-quality evidence that CPAP prevents many long-term outcomes, including cognitive impairment, myocardial infarction, and stroke. Observational studies suggest that patients with symptoms may be particularly likely to experience these preventive benefits with CPAP, but ethical and practical concerns limited the participation of such patients in prior long-term randomized trials. As a result, there is uncertainty about the full benefits of CPAP, and resolving this uncertainty is a key priority for the field. This workshop assembled clinicians, researchers, ethicists, and patients to identify strategies to understand the causal effects of CPAP on long-term clinically important outcomes among patients with symptomatic OSA. Quasi-experimental designs can provide valuable information and are less time and resource intensive than trials. Under specific conditions and assumptions, quasi-experimental studies may be able to provide causal estimates of CPAP's effectiveness from generalizable observational cohorts. However, randomized trials represent the most reliable approach to understanding the causal effects of CPAP among patients with symptoms. Randomized trials of CPAP can ethically include patients with symptomatic OSA, as long as there is outcome-specific equipoise, adequate informed consent, and a plan to maximize safety while minimizing harm (e.g., monitoring for pathologic sleepiness). Furthermore, multiple strategies exist to ensure the generalizability and practicality of future randomized trials of CPAP. These strategies include reducing the burden of trial procedures, improving patient-centeredness, and engaging historically excluded and underserved populations.

Obstructive sleep apnea, intermittent hypoxia and non-alcoholic fatty liver disease.

With the current epidemic of obesity worldwide, the prevalence of various obesity-related diseases is constantly increasing. Obesity remains the strongest phenotypic risk factor in both obstructive sleep apnea (OSA) and non-alcoholic fatty liver disease (NAFLD). In OSA, intermittent hypoxia-reoxygenation and sleep fragmentation, as a result of recurrent episodes of upper airway obstruction during sleep, may give rise to a plethora of metabolic derangements downstream. Intermittent hypoxia (IH) is postulated to be an important mechanistic trigger for potential systemic impact on organs or tissues in OSA, and has served as a useful experimental model for seeking evidence for downstream effects of OSA. This narrative review focuses on the clinical association between OSA and NAFLD, and the role of IH in the progression of NAFLD in lean and diet-induced obese animal models. Understanding the roles of obesity and IH on NAFLD would advance our limited knowledge on the potential health consequences of OSA, a disease which is afflicting more and more people globally, and also in devising effective therapeutic strategies for this progressively common liver condition.

ORMDL3 regulates cigarette smoke-induced endoplasmic reticulum stress in airway smooth muscle cells.

BACKGROUND: Orosomucoid 1-like protein 3 (ORMDL3), a transmembrane protein localized in the endoplasmic reticulum (ER), has been genetically associated with chronic obstructive pulmonary disease (COPD), in addition to childhood-onset asthma. However, the functional role of ORMDL3 in the pathogenesis of COPD is still unknown. OBJECTIVE: Because cigarette smoke is the major risk factor for COPD, we aimed to investigate the role of ORMDL3 in cigarette smoke-induced human airway smooth muscle cell (HASMC) injury. METHODS: The mRNA and protein expression of ORMDL3 was examined in HASMCs from nonsmokers and smokers without or with COPD. Knockdown of ORMDL3 in primary healthy HASMCs was performed using small interfering RNA before exposure to cigarette smoke medium (CSM) for 24 hours. Inflammatory, proliferative/apoptotic, ER stress, and mitochondrial markers were evaluated. RESULTS: Elevation of ORMDL3 mRNA and protein expression was observed in HASMCs of smokers without or with COPD. CSM caused significant upregulation of ORMDL3 expression in healthy nonsmokers. ORMDL3 knockdown regulated CSM-induced inflammation, cell proliferation, and apoptosis. Silencing ORMDL3 led to reduction of CSM-induced ER stress via inhibition of unfolded protein response pathways such as activating transcription factor 6 and protein kinase RNA-like ER kinase. ORMDL3 was also involved in CSM-induced mitochondrial dysfunction via the mitochondrial fission process. CONCLUSIONS: We report the induction of ORMDL3 in HASMCs after cigarette smoke exposure. ORMDL3 may mediate cigarette smoke-induced activation of unfolded protein response pathways during airway smooth muscle cell injury.

Contemporary Concise Review 2020: Sleep.

Obstructive sleep apnoea (OSA) now affects one-seventh of the world's population. Treatment of even mild OSA can improve daytime sleepiness and quality of life. Recent modifications to uvulopalatopharyngoplasty may make it a more widely applicable treatment option in selected patients with OSA. Diet and exercise have effects on sleep apnoea severity independent of weight loss. Insomnia has become increasingly common during the coronavirus disease 2019 (COVID-19) pandemic.

Cigarette smoke induces apoptosis via 18 kDa translocator protein in human bronchial epithelial cells.

AIMS: The 18 kDa translocator protein (TSPO) - also known as peripheral benzodiazepine receptor, is found to be expressed in lung epithelium and pneumocytes, which is closely associated with the mitochondrial permeability transition pore (mPTP) and apoptosis. Cigarette smoking, a key risk factor for the development of chronic obstructive pulmonary disease (COPD), is known to induce apoptosis. We aimed to investigate TSPO subcellular localization and to examine whether cigarette smoke medium (CSM) induce apoptosis via TSPO in airway epithelial cells. MAIN METHODS: TSPO subcellular localization and expression were evaluated using immunofluorescent staining and Western blot analysis respectively. TSPO ligands either PK 11195 (a specific antagonist) or AC-5216 (a specific agonist) were pre-incubated in human bronchial epithelial cells before treating with 2% CSM for measurements of apoptotic cells, mitochondrial membrane potential (ΔΨm), cytoplasmic/mitochondrial reactive oxygen species (ROS) and inflammatory marker interleukin (IL)-8 respectively. KEY FINDINGS: TSPO was localized around the nucleus and overlapped with mitochondria in BEAS-2B cells. CSM caused an increase in apoptotic cells along with elevation of TSPO protein expression. Pretreatment of PK 11195 suppressed while AC-5216 potentiated CSM-induced apoptosis, collapse of ΔΨm, elevation of cytoplasmic/mitochondrial ROS levels and IL-8 release. In support, knockdown of TSPO caused a significant suppression of CSM-induced IL-8 release in BEAS-2B cells. SIGNIFICANCE: The findings suggest that TSPO may play a crucial role in the regulation of cigarette smoke-induced mitochondrial dysfunction via mPTP. Therefore, the development of specific TSPO antagonists like PK11195 may be beneficial to combat smoking-related diseases, such as COPD.

Protective effect of selegiline on cigarette smoke-induced oxidative stress and inflammation in rat lungs in vivo.

BACKGROUND: Cigarette smoke (CS)-induced build-up of oxidative stress is the leading cause of chronic obstructive pulmonary disease (COPD). Monoamine oxidases (MAOs) are novel sources of reactive oxygen species (ROS) due to the production of hydrogen peroxide (H2O2). However, it remains unclear whether MAO signaling is involved in CS-induced oxidative stress in vivo. This study aimed at investigating the impact of selegiline, a selective MAO-B inhibitor, on CS-induced lung oxidative stress and inflammation in vivo and its underlying mechanism. METHODS: Sprague Dawley rats were randomly divided into four groups: saline plus sham air (Saline/air), saline plus cigarette smoke (Saline/CS), selegiline plus sham air (Slg/air) and selegiline plus cigarette smoke (Slg/CS). Rats from Saline/air and Saline/CS groups were intraperitoneally injected with saline (2 mL/kg body weight) while rats from Slg/air and Slg/CS groups were injected with selegiline (2 mg/kg body weight) about 30 min prior to exposure daily. The Saline/air and Slg/air groups were exposed to atmospheric air while the Saline/CS and Slg/CS groups were exposed to mainstream CS generated from the whole body inExpose smoking system (SCIREQ, Canada) for twice daily (each for 1 hour with 20 cigarettes). After 7 days, rats were sacrificed to collect bronchoalveolar lavage (BAL) and lung tissues for the measurement of oxidative/anti-oxidative and inflammatory/anti-inflammatory makers respectively. RESULTS: CS caused significant elevation of MAO-B activity, reduction of total antioxidant capacity (T-AOC) and rGSH/GSSG ratio, and enhancement of superoxide dismutase (SOD) activity in rat lung. Selegiline significantly only reversed CS-induced elevation of MAO-B activity and reduction of rGSH/GSSG ratio. The CS-induced elevation of heme oxygenase-1 (HO-1) and NAD(P)H quinone dehydrogenase 1 (NQO1) expression via nuclear factor erythroid 2-related factor 2 (Nrf2) was also reversed by selegiline. Despite of CS-induced increase in total cell counts, especially the number of macrophages, selegiline had no effect. Selegiline attenuated CS-induced elevation of pro-inflammatory mediators (CINC-1, MCP-1 and IL-6) and restored CS-induced reduction of anti-inflammatory mediator IL-10 in BAL, which was driven through MAPK and NF-κB. CONCLUSIONS: Inhibition of MAO-B may provide a promising therapeutic strategy for CS-mediated oxidative stress and inflammation in acute CS-exposed rat lungs.

Longitudinal multi-gene panel assessment of circulating tumor DNA revealed tumor burden and molecular characteristics along treatment course of non-small cell lung cancer.

BACKGROUND: Most studies associating circulating tumor DNA (ctDNA) with outcome in lung cancer treatment were either cross-sectional or, if longitudinal, only analyzed a limited number of genes. This study evaluated the potential of utilizing ctDNA profiled by a panel of common cancer genes to monitor tumor burden and to reveal molecular characteristics of tumor along treatment course. METHODS: Twenty Chinese non-small cell lung cancer (NSCLC) patients with serial plasma samples collected (I) before starting on either first- or second-line treatment, (II) at stable disease on treatment, and (III) upon disease progression, were analyzed for mutations in ctDNA using the PGDx 64-gene panel. Paired statistics compared mutation profiles between any two of the three time points. RESULTS: Proportions with detectable ctDNA decreased from 65% at baseline to 35% at stable disease and rose to 80% at progression (P=0.012, between stable disease and progression); median ctDNA levels (mutated fragments per mL) were 7.8, 0, and 24.7 at the three time points, respectively (P=0.013 between baseline and progression; P=0.007 between stable disease and progression). Although plasma epidermal growth factor receptor (EGFR) mutations were commonly detected, 15% of patients had mutations other than EGFR detected during progression, such as various types of TP53 mutations. CONCLUSIONS: ctDNA profiling in serial blood samples reflected tumor burden over time, and a multi-gene panel was more sensitive in indicating lung cancer progression on treatment than a single gene approach. The detection of additional oncogenic mutations or their disappearance suggested evolution of tumor heterogeneity along treatment course.

Circulating adipocyte fatty acid-binding protein is reduced by continuous positive airway pressure treatment for obstructive sleep apnea-a randomized controlled study.

PURPOSE: The circulating level of adipocyte fatty acid-binding protein (AFABP), a biomarker with prognostic and therapeutic importance in metabolic disorders, has been shown to be elevated in obstructive sleep apnea (OSA). This randomized controlled study aimed to investigate the effect of continuous positive airway pressure (CPAP) treatment for OSA on AFABP levels. METHODS: Consecutive subjects attending sleep study were invited if they were confirmed to have severe OSA and were free of metabolic diseases. Participants were randomized (1:1) into CPAP or observation group for 4 weeks. Demographics, anthropometric data, and circulating biomarkers were checked at baseline and after the 4-week study period. RESULTS: Ninety subjects were randomized. The mean age was 46 ± 9 years old; 82% were male. Their mean body mass index (BMI) was 29 ± 5 kg/m2. By intention-to-treat approach, the CPAP group showed significant reductions in Epworth sleepiness scale and morning systolic blood pressure (- 7.2 mmHg, - 12.7 to - 1.7 mmHg, p = 0.011), but no significant difference in AFABP, adiponectin, C-reactive protein (CRP), and 8-isoprostane levels. In the per-protocol analysis, when only those who were compliant to CPAP were included, a significant reduction in AFABP (- 7.32 ng/ml, - 13.58, - 1.06, p = 0.023) were found in the CPAP-treated group compared with the control group, along with improvements in clinical parameters. Changes in AFABP were independently associated with both systolic blood pressure (ß = 0.289, p = 0.028) and diastolic blood pressure (ß = 0.217, p = 0.030). CONCLUSION: CPAP therapy used regularly over 4 weeks for severe OSA lowered circulating AFABP level, suggesting a potential beneficial effect of OSA treatment on alleviating metabolic risks. TRIAL REGISTRATION: The research protocol was registered at the National Institutes of Health clinical trials registry (NCT01173432).

Estimation of the global prevalence and burden of obstructive sleep apnoea: a literature-based analysis.

BACKGROUND: There is a scarcity of published data on the global prevalence of obstructive sleep apnoea, a disorder associated with major neurocognitive and cardiovascular sequelae. We used publicly available data and contacted key opinion leaders to estimate the global prevalence of obstructive sleep apnoea. METHODS: We searched PubMed and Embase to identify published studies reporting the prevalence of obstructive sleep apnoea based on objective testing methods. A conversion algorithm was created for studies that did not use the American Academy of Sleep Medicine (AASM) 2012 scoring criteria to identify obstructive sleep apnoea, allowing determination of an equivalent apnoea-hypopnoea index (AHI) for publications that used different criteria. The presence of symptoms was not specifically analysed because of scarce information about symptoms in the reference studies and population data. Prevalence estimates for obstructive sleep apnoea across studies using different diagnostic criteria were standardised with a newly developed algorithm. Countries without obstructive sleep apnoea prevalence data were matched to a similar country with available prevalence data; population similarity was based on the population body-mass index, race, and geographical proximity. The primary outcome was prevalence of obstructive sleep apnoea based on AASM 2012 diagnostic criteria in individuals aged 30-69 years (as this age group generally had available data in the published studies and related to information from the UN for all countries). FINDINGS: Reliable prevalence data for obstructive sleep apnoea were available for 16 countries, from 17 studies. Using AASM 2012 diagnostic criteria and AHI threshold values of five or more events per h and 15 or more events per h, we estimated that 936 million (95% CI 903-970) adults aged 30-69 years (men and women) have mild to severe obstructive sleep apnoea and 425 million (399-450) adults aged 30-69 years have moderate to severe obstructive sleep apnoea globally. The number of affected individuals was highest in China, followed by the USA, Brazil, and India. INTERPRETATION: To our knowledge, this is the first study to report global prevalence of obstructive sleep apnoea; with almost 1 billion people affected, and with prevalence exceeding 50% in some countries, effective diagnostic and treatment strategies are needed to minimise the negative health impacts and to maximise cost-effectiveness. FUNDING: ResMed.

Incident Type 2 Diabetes in OSA and Effect of CPAP Treatment: A Retrospective Clinic Cohort Study.

BACKGROUND: The relationship between OSA and glucose metabolism remains controversial. This retrospective study investigated the relationship between OSA and incident type 2 diabetes (T2D) in a clinic cohort of Chinese adults in Hong Kong, and the effect of long-term CPAP treatment. METHODS: Data for diagnosis of incident T2D and CPAP usage were obtained from the territory-wide electronic health administration system and records of protocolized evaluation of CPAP adherence at the sleep clinic. The relationship between baseline OSA and incident T2D and the effect of CPAP therapy were examined by Cox regression models. Risk of incident T2D over the continuum of apnea-hypopnea index was examined with cubic spline analysis. RESULTS: Of 1,206 subjects with overnight sleep studies and clinical assessment in 2006 through 2013, 152 developed diabetes (median follow-up, 7.3 years). In fully adjusted models, untreated moderate or patients with severe OSA had higher risk of developing diabetes, hazard ratios 2.01 (95% CI, 1.06-3.81) and 2.62 (95% CI, 1.40-4.93) respectively, with a trend to plateau in those with severe OSA. No interaction was demonstrated between OSA and obesity. Regular CPAP use, which was attained in about one-third of subjects with moderate-severe OSA, was associated with reduction of diabetes incidence from 3.41 to 1.61 per 100 person-years, and of adjusted hazard risk to that of non-OSA. CONCLUSIONS: OSA severity independently predicted incident diabetes. Regular long-term CPAP use was associated with reduced risk of incident T2D, after adjustment for various baseline metabolic risk factors and subsequent body weight change.

Rapid versus gradual lung function decline in bronchiolitis obliterans syndrome after haematopoietic stem cell transplantation is associated with survival outcome.

BACKGROUND AND OBJECTIVE: Bronchiolitis obliterans syndrome (BOS) after haematopoietic stem cell transplantation (HSCT) presents with lung function decline. The pattern of lung function decline after BOS diagnosis could impact prognostication of BOS as a complication after HSCT. The aim of this study was to assess the impact of lung function decline on overall survival (OS) in BOS subjects. METHODS: Subjects with BOS were compared to those without BOS and matched for age, gender, primary diagnoses, conditioning regimes and chronic graft versus host disease. Lung function tests at baseline, at BOS diagnosis and every 3 months after HSCT were evaluated. RESULTS: Of the 1461 subjects undergoing allogeneic HSCT (allo-HSCT) between 1998 and 2015, 95 (6.5%) were diagnosed with BOS. A total of 159 matched HSCT recipients without BOS were identified. A 25% decline in FEV1 within the first 3 months after BOS diagnosis would separate BOS subjects into a subgroup with initial rapid decline and another subgroup with initial gradual decline in lung function. The rapid decline group showed lower subsequent lung function parameters and significantly worse OS compared to the gradual decline group (P = 0.013). CONCLUSION: Post-HSCT BOS subjects with initial rapid lung function decline within 3 months after BOS diagnosis will have significantly poorer lung function and worse OS compared to those with initial gradual decline in lung function after BOS diagnosis. HSCT BOS patients with rapid initial decline in lung function warrant closer monitoring for the development of other post-HSCT complications that could affect their survival.

Dysregulation of cardiac lipid parameters in high-fat high-cholesterol diet-induced rat model.

BACKGROUND: Lipid dysregulation is a classical risk factor for cardiovascular disease (CVD), yet scanty evidence existed regarding cardiac lipid metabolism that is directly related to heart damage. Recently, the relationship between dyslipidemia and pro-inflammatory insults has led to further understanding on the CVD-predisposing effects of dyslipidemia. The aims of the present study were to investigate whether high-fat high-cholesterol (HFHC) diet-induced hyperlipidemia would cause heart damage and to study the potential role of local cardiac lipid dysregulation in the occurrence of cellular injury. METHODS: Male Sprague-Dawley rats were divided into normal chow or HFHC diet groups, and sacrificed after 2 or 4 weeks, respectively. Lipid peroxidation marker level was measured. Lipid parameters in the rat hearts were detected. Cardiac damage was evaluated. RESULTS: HFHC diet increased serum levels of cholesterol and free fatty acids (FFAs) and led to systemic oxidative stress and pro-inflammatory status. Cardiac lipid dysregulation, which was characterized by elevated levels of cholesterol and adipocyte (A)- and heart (H)-fatty acid binding proteins (FABPs), occurred after HFHC diet for 4 weeks. Cardiac damage was further evident with elevated circulating H-FABP levels, increased cardiac interstitial fibrosis and the loss of troponin I. CONCLUSION: Our data demonstrated that HFHC diet led to systemic and cardiac lipid dysregulation, accompanied by systemic oxidative and pro-inflammatory stresses, and these may finally cooperate to cause a series of pathological changes of the heart tissue. Our findings suggest that maintenance of lipid regulation may be essential in the prevention of heart damage.

Untreated Obstructive Sleep Apnea Is Associated With Myocardial Injury Independent of Blood Pressure Control in Hypertension.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) and hypertension are independent risk factors of cardiovascular morbidities. This study aims to investigate the relationship between OSA, blood pressure (BP) control, and myocardial injury in patients with difficult-to-control hypertension. METHODS: Patients with hypertension who required three or more medications were prospectively recruited at a tertiary referral center. In-laboratory polysomnography, followed by blood tests for fasting glucose, glycated hemoglobin, lipids, high-sensitivity troponin I (hsTnI), B-type natriuretic peptide (BNP), C-reactive protein, and advanced oxidation protein products were performed. After polysomnography, 24-hour ambulatory BP monitoring was arranged. RESULTS: A total of 98 participants were analyzed, with mean age 51 ± 9 years and body mass index 30 ± 5 kg/m2. Previously undiagnosed severe OSA (apneahypopnea index [AHI] ≥ 30 events/h) was present in 51 patients (52%). hsTnI was negatively correlated with nocturnal dip in systolic BP (r = -.205, P = .048). After controlling for confounders, including BP control, AHI and oxygen desaturation index (ODI) were positively correlated with hsTnI (r = .282, P = .009 and r = .279, P = .010, respectively) and C-reactive protein (r = .302, P = .005 and r = .285, P = .008, respectively), but not with BNP or advanced oxidation protein products. Age, ODI, and loss of nocturnal systolic BP dip were significant determinants of hsTnI level (ß = .225, P = .022; ß = .293, P = .003; and ß = -.215, P = .029; R2 = .151). Age, female sex, 24-hour mean diastolic BP, and metabolic syndrome, but not indices of apnea severity, were predictors of BNP level. CONCLUSIONS: Unrecognized severe OSA was common in patients with difficult-to-control hypertension, and OSA severity was associated with myocardial injury, independent of BP control with medications. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov, Title: A Cross-sectional Study of the Occurrence and Effect of Obstructive Sleep Apnea in Subjects With Resistant Hypertension, Identifier: NCT00843583, URL: https://clinicaltrials.gov/ct2/show/NCT00843583.

Low but not high frequency of intermittent hypoxia suppresses endothelium-dependent, oxidative stress-mediated contractions in carotid arteries of obese mice.

Obstructive sleep apnea is characterized by intermittent hypoxia (IH) during sleep and predisposes to endothelial dysfunction. Obesity is a major risk factor for the occurrence of sleep apnea. The present study compared the functional impact of low- (IH10; 10 hypoxic events/h) and high-frequency (IH60; 60 hypoxic events/h) IH for 4 wk on endothelial function in male C57BL/6 mice with or without high-fat (HF) diet-induced obesity. Mean arterial blood pressure (tail cuff method) was increased in obese mice after IH60 exposure, i.e., HF + IH60 group. The serum levels of the oxidative stress marker malondialdehyde were augmented in lean IH60 and HF groups, with a further increase in HF + IH60 but a reduction in HF + IH10 mice compared with the HF group. Vascular responsiveness was assessed as changes in isometric tension in isolated arteries. Relaxations to the endothelium-dependent vasodilator acetylcholine were impaired in HF + IH60 aortae. Endothelium-dependent contractions (EDC; response to acetylcholine in the presence of the nitric oxide synthase inhibitor l-NAME) in carotid arteries were augmented in the HF group, but this HF-induced augmentation was suppressed by low-frequency IH exposure. The addition of apocynin (antioxidant) reduced EDC in HF and HF + IH60 groups but not in HF + IH10 group. In conclusion, these findings suggest that exposure of obese mice to mild IH exerts preconditioning-like suppression of endothelium-dependent and oxidative stress-mediated contractions. When IH severity increases, this suppression diminishes and endothelial dysfunction accelerates. NEW & NOTEWORTHY The present study demonstrates, for the first time, that low-frequency intermittent hypoxia may exert a preconditioning-like suppression of oxidative stress-induced endothelium-dependent contractions in mice with diet-induced obesity. This relative suppression was diminished as intermittent hypoxia became more severe, and a deleterious effect on endothelial function emerged.