Inhibition of GSK-3尾 ameliorates hepatic ischemia-reperfusion injury through GSK-3尾/尾-catenin signaling pathway in mice

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• 作者：Yong-Xiang Xia ; Ling Lu ; Zheng-Shan Wu ; Li-Yong Pu ; Bei-Cheng Sun ; Xue-Hao Wang ; ^{wangxh@njmu.edu.cn}
• 关键词：glycogen synthase kinase 3 ; beta-catenin ; reperfusion injury ; signal transduction
• 刊名：Hepatobiliary & Pancreatic Diseases International
• 出版年：2012
• 期刊代码：pca182_14993872
• 类别：med
• 出版时间：15 June, 2012
• 卷：11
• 期：3
• 页码：278-284
• 文件大小：453 K

摘要

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Background

Glycogen synthase kinase (GSK)-3尾/尾-catenin signaling regulates ischemia-reperfusion (I/R)-induced apoptosis and proliferation, and inhibition of GSK-3尾 has beneficial effects on I/R injury in the heart and the central nervous system. However, the role of this signaling in hepatic I/R injury remains unclear. The present study aimed to investigate the effects and mechanism of GSK-3尾/尾-catenin signaling in hepatic I/R injury.

Methods

Male C57BL/6 mice (weighing 22-25 g) were pretreated with either SB216763, an inhibitor of GSK-3尾, or vehicle. These mice were subjected to partial hepatic I/R. Blood was collected for test of alanine aminotransferase (ALT), and liver specimen for assays of phosphorylation at the Ser9 residue of GSK-3尾, GSK-3尾 activity, axin 2 and the anti-apoptotic factors Bcl-2 and survivin, as well as the proliferative factors cyclin D1 and proliferating cell nuclear antigen, and apoptotic index (TUNEL). Real-time PCR, Western blotting and immunohistochemical staining were used.

Results

SB216763 increased phospho-GSK-3尾 levels and suppressed GSK-3尾 activity (1880卤229 vs 3280卤272 cpm, P<0.01). ALT peaked at 6 hours after reperfusion. Compared with control, SB216763 decreased ALT after 6 hours of reperfusion (4451卤424 vs 7868卤845 IU/L, P<0.01), and alleviated hepatocyte necrosis and vacuolization. GSK-3尾 inhibition led to the accumulation of 尾-catenin in the cytosol (0.40卤0.05 vs 1.31卤0.11, P<0.05) and nucleus (0.62卤0.14 vs 1.73卤0.12, P<0.05), 尾-catenin further upregulated the expression of axin 2. Upregulation of GSK-3尾/尾-catenin signaling increased Bcl-2, survivin and cyclin D1. Serological and histological analyses showed that SB216763 alleviated hepatic I/R-induced injury by reducing apoptosis (1.4卤0.2%vs 3.6卤0.4%, P<0.05) and enhanced liver proliferation (56卤8%vs 19卤4%, P<0.05).

Conclusions

Inhibition of GSK-3尾 ameliorates hepatic I/R injury through the GSK-3尾/尾-catenin signaling pathway.