Impaired Endothelial Cell Cholesterol Metabolism Promotes Vascular Inflammation in Sleep Apnea

Area of Science:

• Cardiovascular Science
• Sleep Medicine
• Cellular Biology

Background:

• Obstructive sleep apnea (OSA) is common and significantly elevates cardiovascular risk.
• Intermittent hypoxia in OSA impairs endothelial cell (EC) defense against complement, triggering inflammation.
• This process is linked to changes in cellular cholesterol metabolism, but the specifics in OSA patients are unclear.

Purpose of the Study:

• To investigate how intermittent hypoxia affects endothelial cholesterol homeostasis in OSA.
• To determine if these cholesterol alterations contribute to endothelial inflammation in OSA patients.

Main Methods:

• Harvested endothelial cells (ECs) from OSA patients and controls.
• Utilized cultured human umbilical vein ECs exposed to intermittent hypoxia, continuous hypoxia, or normoxia in vitro.

Main Results:

• Intermittent hypoxia causes ER stress, altering protein interactions (VAP-B, Derlin-1, ORP1L) and leading to cholesterol retention in EC endolysosomes.
• Increased EC plasma membrane cholesterol promotes CD59 internalization, enhancing complement deposition and inflammation.
• Positive airway pressure therapy normalized these protein interactions in OSA patients.

Conclusions:

• Altered endothelial cholesterol trafficking and metabolism are key mechanisms driving inflammation and cardiovascular risk in OSA.
• These findings highlight a direct link between OSA, endothelial dysfunction, and cardiovascular complications.