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Angiotensin Receptor Expression and Vascular Endothelial Dysfunction in Obstructive Sleep Apnea.

ABSTRACT: BACKGROUND:Obstructive sleep apnea (OSA) is associated with vascular endothelial dysfunction (VED) in otherwise healthy patients. The role of renin-angiotensin system (RAS) in the OSA induced VED is not well understood. METHODS:Recently diagnosed OSA patients with very low cardiovascular disease (CVD) risk (Framingham score <5%) were studied at diagnosis and after 12 weeks of verified continuous positive airway pressure (CPAP) therapy. Participants underwent biopsy of gluteal subcutaneous tissue at baseline and after CPAP. Microcirculatory endothelial expression of angiotensin receptors type-1 (AT-1) and type-2 (AT-2) was measured in the subcutaneous tissue using quantitative confocal microscopy techniques. The ex-vivo effect of AT-1 receptor blockade (ARB) on endothelial superoxide production was also measured before and after CPAP treatment. RESULTS:In OSA patients (n = 11), microcirculatory endothelial AT1 expression decreased from 873 (200) (fluorescence units) at baseline to 393 (59) units after 12 weeks of CPAP (P = 0.02). AT2 expression did not decrease significantly in these patients (479 (75) to 329 (58) post CPAP (P = 0.08)). The ex-vivo addition of the losartan to the microcirculatory endothelium resulted in decreased superoxide expression in the vascular walls from 14.2 (2.2) units to 4.2 (0.8) P < 0.001; while it had no effect on post-CPAP patient tissue (P = 0.64). CONCLUSIONS:In OSA patients with no to minimal CVD risk, VED is associated with upregulation of AT-1 expression that is reversible with CPAP. Endothelial oxidative stress was reversible with ARB. RAS activation may play an important role in the development of early CVD risk in OSA patients.

SUBMITTER: Khayat RN

PROVIDER: S-EPMC5861541 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Angiotensin Receptor Expression and Vascular Endothelial Dysfunction in Obstructive Sleep Apnea.

Khayat Rami N RN Varadharaj Saradhadevi S Porter Kyle K Sow Angela A Jarjoura David D Gavrilin Mikhail A MA Zweier Jay L JL

American journal of hypertension 20180201 3

<h4>Background</h4>Obstructive sleep apnea (OSA) is associated with vascular endothelial dysfunction (VED) in otherwise healthy patients. The role of renin-angiotensin system (RAS) in the OSA induced VED is not well understood.<h4>Methods</h4>Recently diagnosed OSA patients with very low cardiovascular disease (CVD) risk (Framingham score <5%) were studied at diagnosis and after 12 weeks of verified continuous positive airway pressure (CPAP) therapy. Participants underwent biopsy of gluteal subc ...[more]

PMID: 29036393

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Project description:Untreated and long-lasting obstructive sleep apnea (OSA) may lead to important vascular abnormalities, including endothelial cell (EC) dysfunction, hypertension, and atherosclerosis. We observed a correlation between microcirculatory reactivity and endothelium-dependent release of nitric oxide in OSA patients. Therefore, we hypothesized that OSA affects (micro)vasculature and we aimed to identify vascular gene targets of OSA that could possibly serve as reliable biomarkers of severity of the disease and possibly of vascular risk. Using quantitative RT-PCR, we evaluated gene expression in skin biopsies of OSA patients, mouse aortas from animals exposed to 4-week intermittent hypoxia (IH; rapid oscillations in oxygen desaturation and reoxygenation), and human dermal microvascular (HMVEC) and coronary artery endothelial cells (HCAEC) cultured under IH. We demonstrate a significant upregulation of endothelial nitric oxide synthase (eNOS), tumor necrosis factor-alpha-induced protein 3 (TNFAIP3; A20), hypoxia-inducible factor 1 alpha (HIF-1??? and vascular endothelial growth factor (VEGF) expression in skin biopsies obtained from OSA patients with severe nocturnal hypoxemia (nadir saturated oxygen levels [SaO2]<75%) compared to mildly hypoxemic OSA patients (SaO2 75%-90%) and a significant upregulation of vascular cell adhesion molecule 1 (VCAM-1) expression compared to control subjects. Gene expression profile in aortas of mice exposed to IH demonstrated a significant upregulation of eNOS and VEGF. In an in vitro model of OSA, IH increased expression of A20 and decreased eNOS and HIF-1? expression in HMVEC, while increased A20, VCAM-1 and HIF-1?expression in HCAEC, indicating that EC in culture originating from distinct vascular beds respond differently to IH stress. We conclude that gene expression profiles in skin of OSA patients may correlate with disease severity and, if validated by further studies, could possibly predict vascular risk in OSA patients.

Project description:BackgroundObstructive sleep apnea (OSA) is a highly prevalent disorder that has been associated with an increased risk for cardiovascular morbidity, even in children. However, not all children with OSA manifest alterations in endothelial postocclusive hyperemia, an endothelial nitric oxide synthase (eNOS)-dependent response. Since expression of the eNOS gene is regulated by epigenetic mechanisms and OSA may cause epigenetic modifications such as DNA hypermethylation, we hypothesized that epigenetic modifications in the eNOS gene may underlie the differential vascular phenotypes in pediatric OSA.MethodsAge-, sex-, ethnicity-, and BMI-matched prepubertal children with polysomnographically confirmed OSA and either normal (OSAn) or abnormal (OSAab) postocclusive hyperemic responses, assessed as the time to attain peak reperfusion flow (Tmax) by laser Doppler flowmetry, were recruited. Blood genomic DNA was assessed for epigenetic modifications in the eNOS gene using pyrosequencing. Children with no evidence of OSA or endothelial dysfunction served as a control group.ResultsThe study comprised 36 children with OSA (11 with OSAab and 25 with OSAn) and 35 children in the control group. Overall, the mean age was 7.5 ± 2.4 years, 65% were boys, and 30% were obese; mean apnea-hypopnea index was 18 ± 8.6/h of sleep for the children with OSA. Tmax was 66.7 ± 8.8 s in the OSAab group and 30.1 ± 8.3 s in the OSAn group (P < .001). Pyrosequencing of the proximal promoter region of the eNOS gene revealed no significant differences in six of the seven CpG sites. However, a CpG site located at position -171 (relative to transcription start site), approximating important transcriptional elements, displayed significantly higher methylation levels in the OSAab group as compared with the OSAn or control groups (81.5% ± 3.5%, 74.8% ± 1.4%, and 74.5% ± 1.7%, respectively; P < .001). eNOS mRNA expression levels were assessed in a separate group of children and were significantly reduced in the OSAab group in comparison with the OSAn group.ConclusionsThe presence of abnormal eNOS-dependent vascular responses in children with OSA is associated with epigenetic modifications in the eNOS gene.

Dataset Information

Angiotensin Receptor Expression and Vascular Endothelial Dysfunction in Obstructive Sleep Apnea.

Publications

Angiotensin Receptor Expression and Vascular Endothelial Dysfunction in Obstructive Sleep Apnea.

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