Endothelial Cell Cholesterol Metabolism Dysregulation in Obstructive Sleep Apnea

Obstructive sleep apnea (OSA), a condition affecting a quarter of the Western adults, triples the risk for cardiovascular disease (CVD). OSA is characterized by repetitive cessation of breathing leading to intermittent hypoxia (IH) followed by reoxygenation. IH activates endothelial cells (ECs), a key step in the development and progression of CVD. However, the molecular mechanisms underlying IH-triggered endothelial activation are incompletely understood in OSA. We have reported previously that IH disrupts cellular cholesterol homeostasis leading to free cholesterol accumulation in ECs, which plays a causal role in IH-associated endothelial activation in OSA. Free cholesterol accumulation is cytotoxic and increases CVD risk. Our preliminary data indicate increased level of endoplasmic reticulum (ER) stress response in ECs collected from otherwise healthy OSA patients compared with healthy controls, and IH induces ER stress in EC in vitro model. Considering increasingly recognized role of ER stress in the dysregulation of lipid metabolism, we hypothesize that ER stress mediates IH-induced free cholesterol accumulation in ECs that leads to endothelial activation and increased risk for CVD in OSA. Our preliminary data further show that IH reduces cellular free cholesterol esterification as well as cellular cholesterol efflux, in ECs, which is expected to contribute to endothelial free cholesterol accumulation. In the proposal, we investigate the roles of ER stress in the reduced cholesterol esterification and efflux in OSA-associated IH, and further investigate the molecular mechanisms by which ER stress decreases cholesterol esterification and efflux.