Inhibition of GSK3伪/尾 promotes increased pulmonary endothelial permeability to albumin by reactive oxygen/nitrogen species

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• 作者：Paul Neumann ; Hiba Alsaffar ; Nancy Gertzberg ; Arnold Johnson
• 关键词：Endothelial permeability ; Inflammation ; 尾-catenin ; Lung injury
• 刊名：Pulmonary Pharmacology & Therapeutics
• 出版年：December, 2013
• 年：2013
• 卷：26
• 期：6
• 页码：685-692
• 全文大小：803 K

文摘

Glycogen synthase kinase 3伪/尾 (GSK3伪/尾) is a serine/threonine kinase that participates in numerous processes in many cell types. Importantly, the role of GSK3伪/尾 in homeostatic maintenance of the pulmonary endothelial cell barrier to protein is not known. We tested the hypothesis that GSK3伪/尾 regulates endothelial barrier function by measuring the permeability to albumin of a rat pulmonary microvessel endothelial cell monolayer (PMECM) treated with and without the selective GSK3伪/尾 inhibitor SB 216763 (1.0, 5.0 and 10聽uM) for 1聽h. The treatment with the inhibitor SB 216763 caused a dose dependent decrease in phospho-尾-catenin-Ser^33/37 levels indicating effective suppression of GSK3伪/尾. SB216763聽caused an increase in both permeability to albumin and DCFDA (6-Carboxy-2鈥?7鈥?Dichlorodihydrofluorescein Diacetate, Di(Acetoxymethyl Ester)) oxidation that were prevented by co-treatment with the anti-oxidant tiron or the nitric oxide synthase inhibitor L-NAME (N蠅-nitro-l-arginine-methyl ester). In separate studies PMECMs were treated with the Akt inhibitor triciribine (12.5聽uM) for 1聽h to unmask Akt dependent constitutive suppression of GSK3伪/尾. Triciribine decreased phospho-GSK3伪/尾-Ser²¹/9 (i.e., the product of Akt) which was associated with an increase in phospho-尾-catenin-Ser^33/37 (i.e., the product of GSK3伪/尾) indicating constitutive activity of Akt for GSK3伪/尾-Ser^21/9. The data indicates GSK3伪/尾 inhibition causes increased endothelial monolayer protein permeability which is mediated by reactive oxygen/nitrogen species.