Circulating Angiopoietin-2 (ANG2) increases with PAP sleep apnea treatment
Circulating Angiopoietin-2 (ANG2) increases with PAP sleep apnea treatment: Obstructive sleep apnea (OSA), the most common sleep-related breathing disorder, is becoming increasingly prevalent worldwide due to widespread obesity. It causes a person to repeatedly stop and start breathing during sleep. Positive airway pressure (PAP) is a well-established treatment for OSA patients, using a machine to pump air under pressure into the airway of the lungs. Though effective, the therapy causes large increases in lung volumes during the night that are potentially deleterious. A recent study investigated the impact of PAP therapy on various biomarkers related to alveolar epithelial and endothelial injury. The researchers have shown that Angiopoietin-2 (ANG-2), a marker of endothelial injury and cardiovascular disease risk, increases with continuous positive airway pressure therapy . This finding raises concern for a possible adverse impact of PAP therapy on the vascular endothelium.
Circulating-angiopoietin-2-ang2-increases-with-pap-sleep-apnea-treatment: Effect of positive airway pressure therapy of obstructive sleep apnea on circulating Angiopoietin-2.
Gottlieb DJ, Lederer DJ, Kim JS, Tracy RP, Gao S, Redline S, Jelic S. Sleep Med. 2022 May 16;96:119-121. doi: 10.1016/j.sleep.2022.05.007. Epub ahead of print. PMID: 35636149.
Abstract
Background: Obstructive sleep apnea (OSA) has been identified as a possible contributor to interstitial lung disease. While positive airway pressure (PAP) is effective therapy for OSA, it causes large increases in lung volumes during the night that are potentially deleterious, analogous to ventilator-induced lung injury, although this has not been previously studied. The goal of this study was to assess the impact of PAP therapy on four biomarkers of alveolar epithelial and endothelial injury and extracellular matrix remodeling in patients with OSA.
Methods: In 82 patients with moderate to severe OSA who were adherent to PAP therapy, surfactant protein D, osteopontin, angiopoietin-2, and matrix metalloprotease-7 were measured by ELISA in serum samples collected before and 3- to 6-months after initiation of PAP therapy.
Results: An increase in angiopoietin-2 level of 0.28 ng/mL following PAP therapy was observed (p = 0.007). This finding was replicated in an independent sample of OSA patients. No significant change was detected in surfactant protein D, osteopontin, or matrix metalloprotease-7.
Conclusions: This finding raises concern for a possible adverse impact of PAP therapy on vascular endothelium.
Keywords: Angiopoietin-2; Lung injury; Obstructive sleep apnea; Positive airway pressure.
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Increased Level of Angiopoietin Like Proteins 4 and 8 in People With Sleep Apnea.
Al-Terki A, Abu-Farha M, AlKhairi I, Cherian PT, Sriraman D, Shyamsundar A, Ali S, Almulla F, Tuomilehto J, Abubaker JA. Front Endocrinol (Lausanne). 2018 Nov 13;9:651. doi: 10.3389/fendo.2018.00651. PMID: 30524367; PMCID: PMC6262344.
Abstract
Objective: Obstructive sleep apnea (OSA) is a sleep disorder caused by the complete or partial obstruction of the upper airways. The worldwide prevalence of OSA is increasing due to its close association with obesity epidemic and multiple health complications, such as hypertension, cardiovascular disease, and Type 2 diabetes. Angiopoietin-like protein (ANGPTL)-4 and ANGPTL8 (betatrophin) have been suggested to play a role in the development of these diseases through their role in regulating the metabolism of plasma lipid molecules. This study was designed to evaluate ANGPTL4 and 8 levels in an OSA group and a control group to clarify the effect of OSA on ANGPTL4 and 8 levels. Methods: In total, 74 subjects were enrolled in this study, including 22 age- and body mass index (BMI)-matched controls with the Apnea Hypopnea Index (AHI) score of <5 events/h and 52 subjects with an AHI score of >5 events/h. Sleep apnea was assessed using a portable sleep test. ANGPTL4 and 8 levels were measured in plasma samples using enzyme-linked immunosorbent assay. Results: Mean AHI score (2.5 ± 1.6) in the control group was significantly lower than that in the OSA group (22.9 ± 17.9; p < 0.0001). Leptin, interleukin-(IL) 6, insulin, and HOMA-IR values were higher in the OSA group than in the control group. ANGPTL8 level was higher in the OSA group (1130.0 ± 108.61 pg/mL) than in the control group (809.39 ± 108.78 pg/mL; p = 0.041). Similarly, ANGPTL4 was higher in the OSA group (179.26 ± 12.89 ng/mL) than in the control group (142.63 ±7.99 ng/mL; p = 0.018). Conclusion: Our findings demonstrate that ANGPTL4 and 8 levels were increased in subjects with OSA, suggesting that the upregulation of these lipid metabolism regulators might play a role in lipid dysregulation observed in people with OSA.
Gao S, Emin M, Thoma T, Pastellas K, Castagna F, Shah R, Jimenez A, Patel N, Wei Y, Jelic S. Sleep. 2021 Apr 9;44(4):zsaa286. doi: 10.1093/sleep/zsaa286. PMID: 33351148; PMCID: PMC8033461.
Abstract
Study objective: Obstructive sleep apnea (OSA) is highly prevalent and triples vascular thromboembolic risk. Intermittent hypoxia (IH) during transient cessation of breathing in OSA impairs endothelial protection against complement. Complement activation stimulates the endothelial release of a pro-thrombotic von Willebrand factor (vWF). We investigated whether increased complement activity in OSA promotes the endothelial release of vWF and pro-inflammatory angiopoietin-2. We further investigated whether improving complement protection with statins reverses these changes.
Methods: Using endothelial cells (ECs) and blood collected from OSA patients (n = 109) and controls (n = 67), we assessed whether altered cellular localization of complement inhibitor CD59 in OSA modulates exocytosis of Weibel-Palade bodies (WPB), secretory granules that store vWF and angiopoietin-2. These interactions were also assessed in vitro in ECs exposed to normoxia or IH with or without recombinant complement C9 and with or without atorvastatin.
Results: Circulating levels of angiopoietin-2 were greater in OSA than controls and levels of vWF cleavage products correlated with OSA severity. In cultured ECs, IH enhanced complement-stimulated angiopoietin-2 and vWF release by reducing EC surface and increasing intracellular expression of complement inhibitor CD59. Intracellular CD59 co-localized with WPB in OSA. IH increased binding of intracellular CD59 to syntaxin-3, which dissociated syntaxin-3 from voltage-sensitive calcium channel Cav1.2, and activated WPB exocytosis in a calcium-dependent manner. Atorvastatin reversed IH-enhanced endothelial release of vWF and angiopoietin-2.
Conclusions: IH promotes the complement-mediated release of vWF and angiopoietin-2, which may contribute to pro-thrombotic and pro-inflammatory conditions in OSA. Statin reversed these effects, suggesting a potential approach to reduce cardiovascular risk in OSA.