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H2S production by reactive oxygen species in the carotid body triggers hypertension in a rodent model of sleep apnea.

ABSTRACT: Sleep apnea is a prevalent respiratory disease in which episodic cessation of breathing causes intermittent hypoxia. Patients with sleep apnea and rodents exposed to intermittent hypoxia exhibit hypertension. The carotid body senses changes in blood O2 concentrations, and an enhanced carotid body chemosensory reflex contributes to hypertension in sleep apnea patients. A rodent model of intermittent hypoxia that mimics blood O2 saturation profiles of patients with sleep apnea has shown that increased generation of reactive oxygen species (ROS) in the carotid body enhances the chemosensory reflex and triggers hypertension. CO generated by heme oxygenase-2 (HO-2) induces a signaling pathway that inhibits hydrogen sulfide (H2S) production by cystathionine ?-lyase (CSE), leading to suppression of carotid body activity. We found that ROS inhibited CO generation by HO-2 in the carotid body and liver through a mechanism that required Cys(265) in the heme regulatory motif of heterologously expressed HO-2. We showed that ROS induced by intermittent hypoxia inhibited CO production and increased H2S concentrations in the carotid body, which stimulated its neural activity. In rodents, blockade of H2S synthesis by CSE, by either pharmacologic or genetic approaches, inhibited carotid body activation and hypertension induced by intermittent hypoxia. Thus, our results indicate that oxidant-induced inactivation of HO-2, which leads to increased CSE-dependent H2S production in the carotid body, is a critical trigger of hypertension in rodents exposed to intermittent hypoxia.

SUBMITTER: Yuan G

PROVIDER: S-EPMC5505181 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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H2S production by reactive oxygen species in the carotid body triggers hypertension in a rodent model of sleep apnea.

Yuan Guoxiang G Peng Ying-Jie YJ Khan Shakil A SA Nanduri Jayasri J Singh Amritha A Vasavda Chirag C Semenza Gregg L GL Kumar Ganesh K GK Snyder Solomon H SH Prabhakar Nanduri R NR

Science signaling 20160816 441

Sleep apnea is a prevalent respiratory disease in which episodic cessation of breathing causes intermittent hypoxia. Patients with sleep apnea and rodents exposed to intermittent hypoxia exhibit hypertension. The carotid body senses changes in blood O2 concentrations, and an enhanced carotid body chemosensory reflex contributes to hypertension in sleep apnea patients. A rodent model of intermittent hypoxia that mimics blood O2 saturation profiles of patients with sleep apnea has shown that incre ...[more]

PMID: 27531649

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Project description:BackgroundObstructive sleep apnea is associated with hypertension, inflammation, and increased cardiovascular risk. Continuous positive airway pressure (CPAP) reduces blood pressure, but adherence is often suboptimal, and the benefit beyond management of conventional risk factors is uncertain. Since intermittent hypoxemia may underlie cardiovascular sequelae of sleep apnea, we evaluated the effects of nocturnal supplemental oxygen and CPAP on markers of cardiovascular risk.MethodsWe conducted a randomized, controlled trial in which patients with cardiovascular disease or multiple cardiovascular risk factors were recruited from cardiology practices. Patients were screened for obstructive sleep apnea with the use of the Berlin questionnaire, and home sleep testing was used to establish the diagnosis. Participants with an apnea-hypopnea index of 15 to 50 events per hour were randomly assigned to receive education on sleep hygiene and healthy lifestyle alone (the control group) or, in addition to education, either CPAP or nocturnal supplemental oxygen. Cardiovascular risk was assessed at baseline and after 12 weeks of the study treatment. The primary outcome was 24-hour mean arterial pressure.ResultsOf 318 patients who underwent randomization, 281 (88%) could be evaluated for ambulatory blood pressure at both baseline and follow-up. On average, the 24-hour mean arterial pressure at 12 weeks was lower in the group receiving CPAP than in the control group (-2.4 mm Hg; 95% confidence interval [CI], -4.7 to -0.1; P=0.04) or the group receiving supplemental oxygen (-2.8 mm Hg; 95% CI, -5.1 to -0.5; P=0.02). There was no significant difference in the 24-hour mean arterial pressure between the control group and the group receiving oxygen. A sensitivity analysis performed with the use of multiple imputation approaches to assess the effect of missing data did not change the results of the primary analysis.ConclusionsIn patients with cardiovascular disease or multiple cardiovascular risk factors, the treatment of obstructive sleep apnea with CPAP, but not nocturnal supplemental oxygen, resulted in a significant reduction in blood pressure. (Funded by the National Heart, Lung, and Blood Institute and others; HeartBEAT ClinicalTrials.gov number, NCT01086800 .).

Project description:Study objectivesTo investigate the effects of different intermittent hypoxemia properties on blood pressure (BP) and short-term blood pressure variability (BPV) in severe obstructive sleep apnea (OSA) patients.MethodsNocturnal BP was continuously monitored by measuring pulse transmit time. Apnea-related systolic BP elevation values were used to reflect BPV. Beat-to-beat R-R interval data were incorporated in polysomnography for heart rate variability analysis. The low-frequency/high-frequency band ratio was used to reflect sympathovagal balance. The rate of pulse oxyhemoglobin saturation (SpO₂) decrease was counted as the change in the percentage of SpO₂ per second after obstructive apnea and expressed as the oxygen desaturation rate (ODR). Patients with severe OSA (n = 102) were divided into 2 groups according to the median ODR: faster ODR (FODR group: ODR > 0.37, n = 50) and slower ODR (ODR ≤ 0.37, n = 52).ResultsComparisons between the 2 groups showed significantly higher systolic BP (SBP) values in the FODR group than in the slower ODR group (awake SBP 149.9 ± 18.3 vs 131.8 ± 15.6 mm Hg; asleep SBP: 149.6 ± 19.9 vs 128.7 ± 15.6 mm Hg; both P < .001), as well as short-term BPV (15.0 ± 4.8 vs 11.6 ± 3.6 mm Hg; P < .001), and the prevalence of hypertension (74.0% vs 26.9%; P < .001). Multiple linear regression analyses revealed that after adjusting for body mass index, functional residual capacity, expiratory reserve volume, and baseline SpO2, ODR, as assessed by ΔSpO₂/Δt, had the strongest association with both BP and short-term BPV. Correlation analysis showed that ODR was positively correlated with the low-frequency/high-frequency band ratio (r = .288, P = .003).ConclusionsODR, as a novel hypoxemia profile, was more closely associated with the elevation of BP and BPV in patients with severe OSA. FODR might be associated with enhanced sympathetic activity.Clinical trial registrationRegistry: ClinicalTrials.gov; Name: Characteristics of Obstructive Sleep Apnea Syndrome Related Hypertension and the Effect of Continuous Positive Airway Pressure Treatment on Blood Pressure; URL: https://clinicaltrials.gov/ct2/show/NCT03246022; Identifier: NCT03246022.

Project description:Due to its effects, like an exaggerated negative intrathoracic pressure, sympathetic activation, systemic inflammation, oxidative stress, and endothelial dysfunction, obstructive sleep apnea (OSA) has been involved as a cause in multiple cardiovascular diseases. These diseases include coronary artery disease, hypertension, heart failure, and pulmonary hypertension (PH). Furthermore, OSA often coexists with chronic thromboembolic pulmonary hypertension (CTEPH) in clinical practice. However, few studies focus on OSA and its relationship with CTEPH. This study aims to determine whether OSA has an influence on the clinic status of patients with CTEPH, and to identify what possible factors are associated with OSA in CTEPH. Patients who were newly diagnosed with CTEPH and received overnight polysomnography (PSG) monitoring from September 2015 to December 2017 were enrolled. OSA was defined as apnea-hypopnea index (AHI) of ?5/h and the obstructive events at ?50%. Baseline clinical characteristics and parameters were collected and compared between CTEPH patients with and without OSA. In addition, logistic regression analysis was performed to identify possible factors associated with OSA in CTEPH. Fifty-seven patients with CTEPH were eventually enrolled. Among them, 32 patients were diagnosed with OSA by PSG. CTEPH patients with OSA showed an older age, a higher body mass index (BMI), a higher hemoglobin level, a lower oxygen saturation and a worse World Health Organization functional class (WHO FC) (all P<0.05) when compared to CTEPH patients without OSA. In addition, sleep data including AHI, oxygen desaturation index and minimum oxygen saturation were also statistically different between two groups (all P<0.05). Adjusted for age, sex and BMI, hemoglobin [odd ratio (OR) =1.057, 95% confidence interval (CI): 1.001-1.117, P=0.046], oxygen saturation (OR =0.718, 95% CI: 0.554-0.929, P=0.012), N-terminal pro-brain natriuretic peptide (OR =1.001, 95% CI: 1.000-1.002, P=0.016), mean right atrium pressure (OR =1.284, 95% CI: 1.030-1.600, P=0.026), mean pulmonary arterial pressure (mPAP) (OR =1.087, 95% CI: 1.001-1.180, P=0.048), cardiac index (CI) (OR =0.058, 95% CI: 0.008-0.433, P=0.037), pulmonary vascular resistance (OR =1.004, 95% CI: 1.001-1.007, P=0.014) and WHO FC III-IV (OR =18.550, 95% CI: 2.363-144.128, P=0.005) were associated with OSA in CTEPH. Multivariate logistic regression analysis demonstrated CI (OR =0.051, 95% CI: 0.003-0.868, P=0.040) was independently associated with OSA in CTEPH in addition to age, sex and BMI. OSA may aggravate the clinical status of CTEPH patients to some degree. In turn, a worse hemodynamics, oxygenation state and cardiac function are associated with OSA in CTEPH after being adjusted for age, sex and BMI. Among them, CI is the most important parameter in indicating the coexistence of OSA and CTEPH.

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H2S production by reactive oxygen species in the carotid body triggers hypertension in a rodent model of sleep apnea.

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H2S production by reactive oxygen species in the carotid body triggers hypertension in a rodent model of sleep apnea.

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