Activation of Autophagy by Everolimus Confers Hepatoprotection Against Ischemia-Reperfusion Injury
Activation of Autophagy by Everolimus Confers Hepatoprotection Against Ischemia-Reperfusion Injury
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DOI：
10.1111/ajt.13729
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发表时间：
2016-07-01
影响因子：
8.8
通讯作者：
Kim, S. J.
中科院分区：
文献类型：
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作者：
Lee, S. C.;Kim, K. H.;Kim, S. J.
随着肝脏捐献的标准扩大到包括边缘供体，肝移植物变得特别容易受到肝缺血再灌注损伤（IRI）的影响。然而，目前还没有经过验证的具体措施可以改善肝脏 IRI。在本文中，我们探讨了依维莫司是否对与自噬相关的肝脏 IRI 具有保护作用。在体外和体内肝 IRI 模型中研究了依维莫司的作用。各模型的建立均采用小鼠肝细胞AML12细胞和BALB/c小鼠。在 IRI 诱导的 AML12 细胞中，依维莫司治疗增加了自噬标记物（微管相关蛋白 1 轻链 3 和 p62）的表达，并减少了促凋亡蛋白（裂解的 caspase 3 和裂解的聚 ADP 核糖聚合酶）。使用巴弗洛霉素 A1 或 si-自噬相关蛋白 5 阻断自噬，消除了依维莫司的抗细胞凋亡作用。随后，对 IRI 诱导的肝脏小鼠给予依维莫司，在以下方面提供了肝脏保护作用：(1) 降低促凋亡蛋白的表达，(2) 抑制促炎细胞因子（IL-6 和肿瘤坏死因子）的释放，(3) 降低升高的肝酶（天冬氨酸转氨酶、丙氨酸转氨酶和氨），以及 (4) 恢复肝脏组织病理学。这些发现表明依维莫司通过激活自噬保护肝脏免受肝脏IRI的影响，因此可能成为肝脏IRI的潜在治疗剂。本实验研究表明依维莫司通过激活自噬保护肝脏免受肝脏缺血再灌注损伤，因此可能成为潜在的治疗剂。
As the criteria for liver donation have been extended to include marginal donors, liver grafts are becoming particularly vulnerable to hepatic ischemia-reperfusion injury (IRI). However, no specific measures have been validated to ameliorate hepatic IRI. In this article, we explored whether everolimus has protective effects against hepatic IRI in relation with autophagy. The effects of everolimus were investigated in both in vitro and in vivo hepatic IRI models. Mouse hepatocyte AML12 cells and BALB/c mice were utilized for the establishment of each model. In the IRI-induced AML12 cells, everolimus treatment increased the expressions of autophagic markers (microtubule-associated protein 1 light chain 3 and p62) and decreased pro-apoptotic proteins (cleaved caspase 3 and cleaved poly-ADP ribose polymerase). The blockage of autophagy, using either bafilomycin A1 or si-autophagy-related protein 5, abrogated these anti-apoptosis effects of everolimus. Subsequently, everolimus administration to the hepatic IRI-induced mice provided hepatoprotective effects in terms of (1) decreasing the expressions of pro-apoptotic proteins, (2) inhibiting the release of pro-inflammatory cytokines (IL-6 and tumor necrosis factor-), (3) reducing elevated liver enzymes (aspartate transaminase, alanine transaminase, and ammonia), and (4) restoring liver histopathology. These findings suggest that everolimus protects the liver against hepatic IRI by way of activating autophagy, and thus could be a potential therapeutic agent for hepatic IRI.This experimental study suggests that everolimus protects the liver against hepatic ischemia-reperfusion injury by way of activating autophagy, and thus could be a potential therapeutic agent.