PCSK9 as a new player in intermittent hypoxia-induced vascular alterations

Obstructive sleep apnea syndrome (OSA) is characterized by nocturnal episodes of intermittent hypoxia (IH) and major cardiovascular complications. We recently showed that IH is responsible for increased endothelial permeability and vascular remodeling . The proprotein convertase subtilisine kexine type 9 (PCSK9) has inflammatory effects on arteries. This study aims at characterizing PCSK9 expression in OSA patients and IH models, and to unravel its role in IH-induced endothelial and monocytes dysfunction. PCSK9 level was evaluated by ELISA in serum samples from 58 non-obese OSA patients without comorbidities and 34 control subjects, before and after 6 months of treatment by CPAP. Human Aortic Endothelial Cells (HAEC) and THP-1 monocytes were exposed to IH in vitro (16% O2 for 5 min – 2% O 2 for 5 min, 6 h). Endothelial permeability was evaluated by dextran-FITC passage through HAEC exposed to IH and treated or not with SBC-115076 (10 μM), a chemical inhibitor of PCSK9. THP-1 monocytes migration was evaluated after exposure to IH with or without SBC-115076 and with conditioned media of HepG2 cells exposed to IH or OSA patients’ sera. PCSK9 was overexpressed in OSA patients compared to control subjects (85.2 vs 63.6 ng/mL, P < 0.01) and this difference was abolished after 6 months of CPAP treatment of OSA patients. After adjusting for confounders in multivariate analysis , the presence of OSA, soluble VE-cadherin and LDL-cholesterol were independently associated with an increased level of PCSK9 before treatment. Exposure to IH increased endothelial permeability and THP-1 migration alone or through an endothelial monolayer. Inhibition of PCSK9 was able to reverse these effects. Similar results were obtained with IH-conditioned media and OSA patients’ sera. Recombinant PCSK9 stimulated THP-1 migration under normoxic conditions. OSA is a major determinant 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 endothelial dysfunction and leucocyte activation in vitro.