Inhibition of glycogen synthase kinase 3 ameliorates liver ischemia/reperfusion injury via an energy-dependent mitochondrial mechanism
Inhibition of glycogen synthase kinase 3 ameliorates liver ischemia/reperfusion injury via an energy-dependent mitochondrial mechanism
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DOI：
10.1016/j.jhep.2014.05.017
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发表时间：
2014-10-01
影响因子：
25.7
通讯作者：
Shi, Xueyin
中科院分区：
文献类型：
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作者：
Fu, Hailong;Xu, Haitao;Shi, Xueyin
背景和目标：糖原合成酶激酶-3（GSK-3）介导的肝缺血/再灌注（I/R）过程中的细胞保护机制仍存在争议，特别是在老年器官中。本研究探讨GSK-3在年轻和老龄肝脏中的作用及其可能机制。方法：采用啮齿类动物部分热I/R模型，评价GSK-3在年轻和老龄Sprague-Dawley大鼠肝脏I/R过程中的治疗潜力。这种保护作用在老年动物中不存在，但可以通过在I/R损伤之前输注葡萄糖来恢复。GSK-3抑制剂的保护作用依赖于线粒体代谢调节。事实上，GSK-3的抑制抑制了线粒体通透性转换孔（MPTP）的开放，触发了年轻动物的有丝分裂，而燃料不足抑制了老年动物的线粒体代谢，并使GSK-3相关的保护失活。SB 21和葡萄糖重新激活了衰老肝脏中的线粒体F0 F1-ATP酶和随后的保护级联反应。这些影响被拮抗的ATP酶抑制剂和MPTP opener.Conclusions：GSK-3抑制在肝I/R损伤的保护是能量依赖性的，特别是在衰老的肝脏。这些发现表明GSK-3相关线粒体能量稳态的关键作用，这可能为GSK-3抑制剂在手术环境中保护肝功能的临床应用提供新的线索，特别是对于老年患者。(C)2014年欧洲肝脏研究协会。Elsevier B. V.出版，保留所有权利。
Background & Aims: The mechanisms of glycogen synthase kinase-3 (GSK-3)-mediated cytoprotection during liver ischemia/reperfusion (I/R) remain controversial, particularly in older organs. This study explores the role and potential mechanisms of GSK-3 in young and aging livers.Methods: A rodent partial warm I/R model was used to evaluate the therapeutic potential of GSK-3 modulation during hepatic I/R in young and aging Sprague-Dawley rats.Results: GSK-3 inhibition through IPC or SB216763 (SB21) preconditioning protected young rats from I/R-induced liver injury. This protection was absent in old animals but could be restored by glucose infusion prior to the I/R insult. The protection conferred by GSK-3 inhibition depended on mitochondrial metabolism regulation. Indeed, the inhibition of GSK-3 suppressed mitochondrial permeability transition pore (MPTP) opening, triggering mitohormesis in young animals, whereas insufficient fuel suppressed mitochondrial metabolism and inactivated the GSK-3-related protection in old animals. SB21 and glucose reactivated the mitochondrial F0F1-ATPase and subsequent protective cascades in the senescent liver. These effects were antagonized by an ATPase inhibitor and by an MPTP opener.Conclusions: The protection conferred by GSK-3 inhibition during hepatic I/R insult is energy dependent, particularly in senescent livers. These findings demonstrate a key role for GSK-3-related mitochondrial energy homeostasis, which may shed new light on the clinical use of GSK-3 inhibitors to protect liver function in surgical settings, particularly for older patients. (C) 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.