טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentGolan-Shani Orit
SubjectAtherosclerotic Phenotype of Monocytes in Obstructive Sleep
Apnea Syndrome
DepartmentDepartment of Medicine
Supervisor Dr. Lena Lavie
Full Thesis textFull thesis text - English Version


Abstract

Obstructive sleep apnea (OSA) is characterized by intermittent hypoxia (IH) during sleep, which induces free radical generation and increased oxidative stress and inflammation. OSA is implicated as one of the risk factors responsible for the initiation and progression of atherosclerosis leading to cardiovascular disease.

Monocytes play a crucial role in the development of atherosclerosis. In response to activating stimuli, they produce pro-inflammatory cytokines and reactive oxygen species (ROS). Additionally, they express adhesion molecules which contribute to their increased adherence to endothelial cells (ECs). Then, monocytes differentiate into macrophages in the subendothelial space, take up Oxidized-LDL (Ox-LDL) and transform into foam cells.

The aim of the present study was to investigate the mechanisms involved in the activation of OSA monocytes which lead to cardiovascular disease.

Monocytes of co-morbidity free OSA patients exhibited an increase in the expression of the inflammatory cytokines TNF-α and IL-10. In addition, expression of the adhesion molecule CD11b, the Ox-LDL scavenger receptor CD36 and Ox-LDL uptake by monocytes were increased as compared to matched controls. Additionally, Ox-LDL levels in the plasma were also higher in OSA patients as well as foam cell formation that was also positively correlated with OSA severity.

Intermittent hypoxia and sustained hypoxia (SH) in vitro greatly affected foam cell formation of healthy individuals as compared to normoxia. Yet, SH was more effective than IH. Additionally, ECs treated with IH or SH in vitro led to a significant increase in THP-1 monocyte adhesion. However, IH in vitro was more effective than SH. TNF-α and Ox-LDL were implicated in increased THP-1 monocyte adhesion to ECs. A combined IH/TNF-α led to a further increase in THP-1 monocyte adhesion to ECs. On the other hand, Ox-LDL was a stronger stimulus than IH or SH and thus overcome their effects. Moreover, the involvement of ROS and NFκB were implicated, at least partly, in the adhesion of THP-1 monocyte to IH treated ECs.

In conclusion, a pro-atherogenic monocyte phenotype is evident in OSA via increased inflammatory cytokines, adhesion molecules, scavenger receptors, Ox-LDL uptake and increased foam cell formation as compared to control subjects. Similar findings in IH in vitro were observed for foam cell formation. Also, increased adhesion of THP-1 monocytes to IH treated ECs was demonstrated. These processes are likely a part of the mechanisms responsible for the pathogenesis of cardiovascular morbidity in patients with OSA.