Tobacco smoke cooperates with interleukin-1beta to alter beta-catenin trafficking in vascular endothelium resulting in increased permeability and induction of cyclooxygenase-2 expression in vitro and in vivo.
Cigarette smoking affects all phases of atherosclerosis from endothelial dysfunction to acute occlusive clinical events. We explored activation by exposure to tobacco smoke of two genes, beta-catenin and COX-2, that play key roles in inflammation and vascular remodeling events. Using both in vivo and in vitro smoke exposure, we determined that tobacco smoke (TS) induced nuclear beta-catenin accumulation and COX-2 expression and activity and moreover interacted with IL-1beta to enhance these effects. Exposure of cardiac endothelial cells to tobacco smoke plus IL-1beta (TS/IL-1beta) enhanced permeability of endothelial monolayers and disrupted membrane VE-cadherin/beta-catenin complexes, decreased beta-catenin phosphorylation, and increased phosphorylation of GSK-3beta, Akt, and EGFR. Transfection of endothelial cells with beta-catenin-directed small interfering RNA (siRNA) suppressed TS/IL-1beta-mediated effects on COX-2 modulation. Inhibitors of EGFR and phosphatidylinositol-3-kinase also abolished both the TS/IL-1beta-mediated modulation of the Akt/GSK-3beta/beta-catenin pathway and enhancement of COX-2 expression. Moreover, increased levels of Akt and GSK-3beta phosphorylation, nuclear beta-catenin accumulation, COX-2 expression, and IL-1beta were observed in cardiovascular tissue of ApoE-/- mice exposed to cigarette smoke daily for 2 wk. Our results suggest a novel mechanism by which cigarette smoking can induce proinflammatory and proatherosclerotic effects in vascular tissue.
Barbieri
Silvia S
SS
Division of Hematology-Medical Oncology, Weill Medical College of Cornell University, 1300 York Ave., New York, NY 10021, USA.
Weksler
Babette B
BB
D000818:Animals; D000831:Animals, Newborn; D050197:Atherosclerosis; D051546:Cyclooxygenase 2 / Q000235:genetics*; D004730:Endothelium, Vascular / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation; D053583:Interleukin-1beta / Q000502:physiology*; D051379:Mice; D009206:Myocardium / Q000166:cytology; D010539:Permeability; D010766:Phosphorylation; D021381:Protein Transport; D015398:Signal Transduction; D012906:Smoke / Q000009:adverse effects*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*; D014026:Nicotiana
D053583:Interleukin-1beta; D012906:Smoke; D051176:beta Catenin; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2