Impaired Endothelial Cell Cholesterol Metabolism Promotes Vascular Inflammation in Sleep Apnea

BACKGROUND: Obstructive sleep apnea (OSA) is highly prevalent and triples cardiovascular risk. Intermittent hypoxia during apneas impairs endothelial cell (EC) protection against complement, which initiates endothelial inflammation and increases cardiovascular risk. This process appears to be linked to altered cellular cholesterol metabolism. However, whether and how intermittent hypoxia alters endothelial cholesterol homeostasis and whether those changes affect endothelial inflammation in patients with OSA are unclear. METHODS: ECs were harvested from the forearm vein from patients with OSA (n=24; age, 44±14 years; 38% female; body mass index, 36±10 kg/m 2 ) and OSA-free controls (n=19; age, 39±14 years; 74% female; body mass index, 29±9 kg/m 2 ). Cultured human umbilical vein ECs exposed to intermittent hypoxia (alternating 30-minute 21% O 2 for normoxia/30-minute 2% O 2 for hypoxia for 8 hours), 2% O 2 for 8 hours (continuous hypoxia), or normoxia were used as the in vitro model. RESULTS: Intermittent hypoxia–induced endoplasmic reticulum stress increases interaction of endoplasmic reticulum-bound VAP-B (vesicle-associated membrane protein-associated protein B) with Derlin-1 (degradation in endoplasmic reticulum protein 1), which, in turn, impairs VAP-B interaction with endolysosomal compartment-bound ORP1L (oxysterol-binding protein-related protein 1 long form), leading to retention of cholesterol in the endolysosomal compartment in ECs in OSA. The consequent increase in cholesterol content in the EC plasma membrane promotes internalization of the complement inhibitor CD59, thereby increasing deposition of the terminal complement membrane attack complex on ECs and initiating inflammation. Low levels of positive airway pressure therapy reversed OSA-induced alteration in interactions of VAP-B with both Derlin-1 and ORP1L in patients with OSA. CONCLUSIONS: Using a direct approach to study endothelium, we have identified altered endothelial intracellular cholesterol trafficking and metabolism as mechanisms underlying reduced protection against complement activity and increased endothelial inflammation, which, over time, increases cardiovascular risk in OSA.