PCSK9 as a mediator of monocytes transendothelial activation in obstructive sleep apnoea: A translational study.

Obstructive sleep apnoea (OSA) causes intermittent hypoxia (IH) during sleep which is the main trigger for associated cardiovascular complications. IH increases endothelial permeability and vascular remodelling. The proprotein convertase subtilisine kexine type 9 (PCSK9) is capable of promoting vascular inflammation. This study aims at characterizing PCSK9 expression in OSA patients and cellular models exposed to IH for unravelling PCSK9 role in monocytes migration and endothelial permeability. PCSK9 levels were evaluated by ELISA in serum from 48 OSA patients without comorbidities and 27 control subjects, before and after 6 months of treatment by Continuous Positive Airway Pressure (CPAP). Human Aortic Endothelial Cells and THP-1 monocytes were exposed to IH in vitro. Monocyte migration was studied after IH or OSA patients' sera exposure, treated or not with inhibitors of PCSK9 (SBC-115076 or anti-PCSK9 mAb1), and endothelial permeability was evaluated by dextran-FITC passage. PCSK9 was elevated in OSA patients compared to control subjects and this difference was abolished after 6 months of CPAP treatment. In multivariate analysis, the presence of OSA was independently associated with an increased level of PCSK9 at baseline. Exposure to IH increased endothelial permeability, and both IH and OSA patient's sera increased THP-1 migration. IH upregulated ICAM1, CD163 and SOD2 gene and SOD2 protein expression in THP-1 cells. All these effects were reversed by PCSK9 inhibition. OSA is one of the determinants of increased PCSK9 in humans. PCSK9 inhibition reverses IH-induced endothelial permeability and monocyte migration, suggesting that PCSK9 could be a key player in IH-induced vascular remodelling.