1,721,026 research outputs found
Tobacco smoke enhances interleukin-1beta-induced cyclooxygenase-2 expression by AKT/GSK-3beta/beta-catenin pathway in vitro and in vivo
No full textInflammatory cytokines present in smokers’ serum modulate cyclooxygenase-2 expression via NADPH-oxidase in endothelial cells
No full textBackground: Cigarette smoking modulates inflammation and endothelial dysfunction, events implicated in athero-thrombotic disease.1,2 Recently, endothelial dysfunction has been related to reactive oxygen species (ROS)3 and to prostanoids produced via cyclooxygenase-2 (COX-2)4. We hypothesized that inflammatory cytokines presents in smokers’ serum induce ROS generation in endothelium by activation of NADPH oxidase with consequent COX-2 expression.
Methods: Serum levels of interleukin-1beta (IL-1) and tumor necrosis factor alpha (TNF) were measured in 18 male volunteers (9 smokers and 9 non smokers). Human bone marrow endothelial cells (HBMEC) were exposed to serum from smokers or non-smokers, and ROS production (dichlorofluorescein fluorescence), NADPH oxidase activation (translocation of p47phox), COX-2 protein (Western blot) and mRNA (quantitative RT-PCR) were evaluated.
Results: Serum from smokers compared with non smokers showed higher levels of IL-1 (P<0.05) and TNF (P<0.0008) and greater ability to induce ROS generation (P<0.002), translocation of p47phox from cytoplasm to plasma membrane (P<0.01), and increase COX-2 mRNA and protein (P<0.002) in HBMEC. Serum-induced ROS production and COX-2 mRNA by HBMEC correlated positively with IL-1 (r=0.723, P<0.002 and r=0.707, P<0.002) and TNF ( =0.781, P<0.0002 and r=0.772, P<0.0003). Moreover, there was a significant positive correlation between ROS generation and COX-2 mRNA (r=0.822, P<0.006). Simultaneous immunoneutralization of IL and TNF prevented ROS formation and COX-2 expression induced by smoker’s serum. Inhibitors of NADPH oxidase and p47phox siRNA dramatically diminished smokers’ serum-mediated endothelial ROS production and COX-2 expression.
Conclusion: Our results suggest an essential role of inflammatory cytokines in the modulation of endothelial dysfunction induced by smoking.
References
1. J. A. Ambrose et R. S. Barua. The pathophysiology of cigarette smoking and cardiovascular disease: an update. J. Am. Coll. Cardiol., 43, 1731-1737, 2004.
2. P.W. Wilson. Smoking, smoking cessation, and risk of cardiovascular disease. Curr. Treat. Options Cardiovasc. Med., 8, 276-281, 2006.
3. S.S. Barbieri, L. Ruggiero, E. Tremoli, B.B. Weksler. Suppressing PTEN activity by tobacco smoke plus interleukin-1beta modulates dissociation of VE-cadherin/beta-catenin complexes in endothelium. Arterioscler Thromb Vasc Biol., 28, 732-738, 2008
4. S. S. Barbieri et B. B Weksler. Tobacco smoke cooperates with interleukin-1 to alter β-catenin trafficking in vascular endothelium resulting in increased permeability and induction of ciclooxigenase-2 expression in vitro and in vivo. FASEB J., 21, 1-13, 200
Tobacco smoke cooperates with interleukin-1beta to alter B-catenin trafficking in vascular endothelium resulting in increased permeability and induction of cyclooxygenase-2 expression in vitro and in vivo
No full textTobacco smoke cooperates with interleukin-1β to alter β-catenin trafficking in vascular endothelium resulting in increased permeability and induction of cyclooxygenase-2 expression in vitro and in vivo
No full textCigarette 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, β-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 β-catenin accumulation and COX-2 expression and activity and moreover interacted with IL-1 β to enhance these effects. Exposure of cardiac endothelial cells to tobacco smoke plus IL-1β (TS/IL-1β) enhanced permeability of endothelial monolayers and disrupted membrane VE-cadherin/β-catenin complexes, decreased β-catenin phosphorylation, and increased phosphorylation of GSK-3β, Akt, and EGFR. Transfection of endothelial cells with β-catenin-directed small interferring RNA (siRNA) suppressed TS/IL-1β-mediated effects on COX-2 modulation. Inhibitors of EGFR and phosphatidylinositol-3- kinase also abolished both the TS/IL-1β-mediated modulation of the Akt/GSK-3β/β-catenin pathway and enhancement of COX-2 expression. Moreover, increased levels of Akt and GSK-3β phosphorylation, nuclear β-catenin accumulation, COX-2 expression, and IL-1β 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 tissu
Reactive oxygen species mediate cyclooxygenase-2 induction during monocyte to macrophage differentiation : critical role of NADPH oxidase
No full textOBJECTIVE: The objective of this study was to explore the relationship between monocyte differentiation into macrophages and cyclooxygenase-2 (Cox-2) expression, based upon the observation that high amounts of this enzyme, colocalizing mainly with macrophages, have been found in human atherosclerotic lesions. Moreover, the hypothesis that reactive oxygen species (ROS) could be important as mediators of Cox-2 expression during monocyte differentiation was verified. Although ROS are known as modulators of gene expression profile, their involvement in monocyte differentiation has not been explored previously. METHODS: Human adherent monocytes and the promonocytic cell line U937 were differentiated into macrophages by phorbol ester (PMA). Cox-2 was evaluated in terms of protein, mRNA and activity. Intracellular ROS formation was measured by the oxidant sensitive dye 2',7'-dichlorofluorescein diacetate. NADPH oxidase subunit p47(phox) was evaluated by Western blot analysis. RESULTS: Functionally active Cox-2 is expressed during PMA-induced monocyte transition into macrophages and ROS driven by the NADPH oxidase play a critical role in this event. CONCLUSION: Monocyte differentiation into macrophages, possibly triggered by unquenched ROS, may contribute to the increased inflammatory response within atheromata
Reactive oxygen species mediate cyclooxygenase-2 induction during monocyte transition into macrophages: critical role for NADPH oxidase
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Tobacco smoke interaction with Interkeukin-1beta promotes dissociation of VE-Cadherin VE-cadherin and beta-catenin complexes, suppression of PTEN activity and induction of COX-2 expression through the ROS pathway
No full textTobacco smoke interaction with interleukin-1beta promotes dissociation of VE-cadherin/beta-catenin complexes, suppression of PTEN activity and COX-2 expression though the ROS pathway
No full textSuppressing PTEN activity by tobacco smoke plus interleukin-1beta modulates dissociation of VE-cadherin/beta-catenin complexes in endothelium
No full textObjectives. Tobacco smoke (TS) interacts with inflammatory cytokines to produce endothelial dysfunction. We hypothesized that interleukin-1β (IL-1β) plus TS (TS/IL-1β) induces disassembly of endothelial junctional complexes of VE-cadherin/β-catenin by suppression of PTEN activity and investigated molecular mechanisms that modulate PTEN-deactivation in this situation. Methods and Results. TS/IL-1β exposure, which disrupted adherens junctions and induced nuclear β-catenin accumulation, increased tyrosine phosphorylation (p-Tyr) of VE-cadherin and β-catenin, and reduced PTEN activity. Overexpression or silencing of PTEN modulated p-Tyr of both VE-cadherin and β-catenin, changed assembly of adherens junction complexes, and altered nuclear β-catenin accumulation. In addition, inhibiting ROS production stimulated by TS/IL-1β decreased activation of Src, EGFR and p38MAPK, phosphorylation of PTEN, VE-cadherin and_-catenin, and abrogated the effect of TS/IL-1β to disorganize adherens junctions, resulting in reduced endothelial permeability and decreased nuclear β-catenin accumulation. Finally, exposure of ApoE-/- mice to cigarette smoke–induced phosphorylation of Src, EGFR, p-38MAPK, PTEN, and β-catenin, and disrupted VE-cadherin/β-catenin complexes in cardiovascular tissue. Conclusions. TS interaction with IL-1β modulates PTEN activity though the ROS/Src/EGFR-p38MAPK pathway. PTEN deactivation is essential to increase VE-cadherin and β-catenin p-Tyr and to disassemble VE-cadherin/β-catenin membrane complexes, events that lead to accumulation of β-catenin within the nucleu
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