Statins Restore Endothelial Protection against Complement Activity in Obstructive Sleep Apnea: A Randomized Clinical Trial.

Rationale: Increased cardiovascular risk in obstructive sleep apnea (OSA) persists after continuous positive airway pressure (CPAP) and alternative therapies are needed. Impaired endothelial protection against complement is a cholesterol-dependent process that initiates endothelial inflammation in OSA, which increases cardiovascular risk. Objectives: To investigate directly whether lowering cholesterol improves endothelial protection against complement and its proinflammatory effects in OSA. Methods: Newly diagnosed patients with OSA (n = 87) and OSA-free controls (n = 32) participated. Endothelial cells and blood were collected at baseline, after 4 weeks of CPAP therapy, and again after 4 weeks of 10 mg atorvastatin versus placebo using a randomized, double-blind, parallel-group design. Primary outcome was the proportion of a complement inhibitor, CD59, on the endothelial cell plasma membrane in OSA patients after 4 weeks of statins versus placebo. Secondary outcomes were complement deposition on endothelial cells and circulating levels of its downstream proinflammatory factor, angiopoietin-2, after statins versus placebo. Results: Baseline expression of CD59 was lower, whereas complement deposition on endothelial cells and levels of angiopoietin-2 were greater, in patients with OSA compared with controls. CPAP did not affect expression of CD59 or complement deposition on endothelial cells in patients with OSA, regardless of adherence. Compared with placebo, statins increased expression of endothelial complement protector CD59 and lowered complement deposition in patients with OSA. Good CPAP adherence was associated with increased angiopoietin-2 levels, which was reversed by statins. Conclusions: Statins restore endothelial protection against complement and reduce its downstream proinflammatory effects, suggesting a potential approach to reduce residual cardiovascular risk after CPAP in patients with OSA. Clinical trial registered with www.clinicaltrials.gov (NCT03122639).

Complement promotes endothelial von Willebrand factor and angiopoietin-2 release in obstructive sleep apnea.

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.

Low-grade chronic inflammation is attenuated by exercise training in obese adults through down-regulation of ASC gene in peripheral blood: a pilot study.

BACKGROUND: Obesity is characterized by low-grade chronic inflammation and an excess of adipose tissue. The ASC gene encodes a protein that is part of the NLRP3 inflammasome, a cytosolic multiprotein complex that is associated with inflammation and metabolic alterations. To our knowledge, there is no evidence regarding ASC gene activity in obese adults in response to lifestyle modifications. PURPOSE: To evaluate the effect of hypocaloric diet and moderate-intensity structured exercise intervention on ASC gene expression and inflammatory markers in obese adults. METHODS: Thirty-seven obese individuals aged 25 to 50 years were randomized to the hypocaloric diet exercise group or hypocaloric diet group. The participants underwent a 4-month follow-up. Electrical bioimpedance was used for body composition analysis. Biochemical data were analyzed by dry chemistry and insulin levels by ELISA. ASC gene expression from peripheral blood was performed using real-time PCR. Dietary data was collected through questionnaires and analyzed using the Nutritionist Pro™ software. Quantification of cytokines was conducted using Bio-Plex Pro™ Human cytokine. The Astrand-Ryhming test was used to estimate the maximum oxygen volume and design the moderate-intensity structured exercise program ~ 75% heart rate (HR) RESULTS: After the intervention, both study groups significantly improved body composition (decreased weight, fat mass, waist circumference and abdominal obesity, p < 0.05). Besides, the diet-exercise group significantly decreased ASC mRNA expression, MCP-1, and MIP-1ß inflammatory cytokines compared to the diet group (p < 0.05). While in the diet group, MCP-1 and IL-8 exhibited significantly decreased levels (p < 0.05). In the diet-exercise group, a positive correlation between the atherogenic index and waist circumference was found (r = 0.822, p = 0.011), and a negative correlation was observed between the delta of ASC mRNA expression and IL-10 levels at the end of the intervention (r = - 0.627, p = 0.019). CONCLUSION: Low-grade chronic inflammation was attenuated through individualized exercise prescription and our findings highlight the role of the ASC gene in the inflammation of obese adults. TRIAL REGISTRATION: ClinicalTrials.gov , number NCT04315376 . Registered 20 March 2020-retrospectively registered.