Tobacco 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
Tobacco 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
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DOI：
10.1096/fj.06-7557com
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发表时间：
2007-06-01
期刊：
影响因子：
4.8
通讯作者：
Weksler, Babette B.
中科院分区：
文献类型：
--
作者：
Barbieri, Silvia S.;Weksler, Babette B.
吸烟影响动脉粥样硬化的所有阶段，从内皮功能障碍到急性闭塞性临床事件。我们研究了暴露于烟草烟雾中的两种基因β-连环蛋白和考克斯-2的激活，这两种基因在炎症和血管重塑事件中起关键作用。使用体内和体外烟雾暴露，我们确定烟草烟雾（TS）诱导细胞核β-连环蛋白的积累和考克斯-2的表达和活性，并与IL-1 β相互作用，以增强这些作用。心脏内皮细胞暴露于烟草烟雾加IL-1 β（TS/ IL-1 β）增强了内皮细胞单层的通透性，破坏了膜VE-钙粘蛋白/β-连环蛋白复合物，降低了β-连环蛋白磷酸化，增加了GSK-3 β、Akt和EGFR的磷酸化。用β-连环蛋白定向的小干扰RNA（siRNA）转染内皮细胞抑制TS/ IL-1 β介导的对考克斯-2调节的作用。EGFR和磷脂酰肌醇-3-激酶的抑制剂也消除了TS/ IL-1 β介导的Akt/GSK-3 β/β-连环蛋白途径的调节和考克斯-2表达的增强。此外，在每天暴露于香烟烟雾2周的ApoE（-/-）小鼠的心血管组织中观察到Akt和GSK-3 β磷酸化水平增加、细胞核β-连环蛋白积累、考克斯-2表达和IL-1 β。我们的研究结果提示了一种新的机制，通过这种机制，吸烟可以诱导血管组织中的促炎症和促动脉粥样硬化作用。Barbieri，S.美国，韦克斯勒，B。B。烟草烟雾与白细胞介素-1 β协同改变β-连环蛋白在血管内皮中的运输，导致体外和体内通透性增加和环氧合酶-2表达的诱导。
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-1 beta to enhance these effects. Exposure of cardiac endothelial cells to tobacco smoke plus IL-1 beta (TS/ IL-1 beta) enhanced permeability of endothelial monolayers and disrupted membrane VE-cadherin/beta-catenin complexes, decreased beta-catenin phosphorylation, and increased phosphorylation of GSK-3 beta, Akt, and EGFR. Transfection of endothelial cells with beta-catenin-directed small interferring RNA (siRNA) suppressed TS/ IL-1 beta-mediated effects on COX-2 modulation. Inhibitors of EGFR and phosphatidylinositol- 3-kinase also abolished both the TS/ IL-1 beta-mediated modulation of the Akt/GSK-3 beta/beta-catenin pathway and enhancement of COX-2 expression. Moreover, increased levels of Akt and GSK-3 beta phosphorylation, nuclear beta-catenin accumulation, COX-2 expression, and IL-1 beta 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, S. S., Weksler, B. B. Tobacco smoke cooperates with interleukin-1 beta to alter beta- catenin trafficking in vascular endothelium resulting in increased permeability and induction of cyclooxygenase- 2 expression in vitro and in vivo.