Meccanismi di disfunzione endoteliale e aterosclerosi: ruolo dello stress ossidativo e dell'infiammazione

Cigarette smoking is an important risk factor for atherosclerosis, a chronic inflammatory disease. However the underlying factors of this effect are unclear. It has been hypothesized that water-soluble components of cigarette smoke can directly promote oxidative stress in vasculature and blood cells. Aim of this study was to study the relationship between oxidative stress and inflammation in a group of young smokers. To do this we evaluated: 1) the oxidation products of phospholipids (oxPAPC) in peripheral blood mononuclear cells (PBMC); 2) their role in causing PBMC reactive oxygen species (ROS)generation and changes in GSH; 3) the expression of the transcription factor NF-E2-related factor 2 (Nrf2) and of related antioxidant genes (ARE); 4) the activation of NF-kB and C-reactive protein (CRP) values. We studied 90 healthy volunteers: 32 non-smokers, 32 moderate smokers (5–10 cigarettes/day) and 26 heavy smokers (25–40 cigarettes/day). OxPAPC was higher in moderate smokers and heavy smokers than in non-smokers (p,0.01), the highest values being in heavy smokers (p,0.01). In in vitro studies oxPAPC increased ROS generation via NADPH oxidase activation. GSH in PBMC and plasma was lower in moderate smokers and heavy smokers than in non-smokers (p,0.01), the lowest values being in heavy smokers (p,0.01). Nrf2 expression in PBMC was higher inmoderate smokers than in non-smokers (p,0.01), but not in heavy smokers, who had the highest levels of NF-kB and CRP (p,0.01). In in vitro studies oxPAPC dose-dependently increased NF-kB activation, whereas at the highest concentrations.Nrf2 expression was repressed. The small interference (si) RNA-mediated knockdown of NF-kB/p65 increased about three times the expression of Nrf2 stimulated with oxPAPC. Cigarette smoke promotes oxPAPC formation and oxidative stress in PBMC. This may cause the activation of NF-kB that in turn may participate in the negative regulation of Nrf2/ARE pathway favouring inflammation.