Activation of Autophagy by Everolimus Confers Hepatoprotection Against Ischemia–Reperfusion Injury.
Activation of Autophagy by Everolimus Confers Hepatoprotection Against Ischemia–Reperfusion Injury.
复制标题
DOI：
10.1097/01.tp.0000543673.77833.b8
复制
发表时间：
2018-07
期刊：
影响因子：
6.2
通讯作者：
Kee-Hwan Kim;Say-June Kim;Soo-Ho Lee
中科院分区：
文献类型：
--
作者：
Kee-Hwan Kim;Say-June Kim;Soo-Ho Lee
随着肝脏捐献的标准已经扩展到包括边缘供体，肝脏移植物变得特别容易受到肝脏缺血再灌注损伤（IRI）的影响。然而，尚未验证改善肝脏IRI的具体措施。在这篇文章中，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。在体外和体内肝脏IRI模型中研究了依维莫司的作用。用小鼠肝细胞AML 12细胞和BALB/c小鼠建立模型。在IRI诱导的AML 12细胞中，依维莫司处理增加了自噬标志物（微管相关蛋白1轻链3和p62）的表达，并降低了促凋亡蛋白（裂解的半胱天冬酶3和裂解的聚ADP核糖聚合酶）的表达。使用巴弗洛霉素A1或si-自噬相关蛋白5阻断自噬，消除了依维莫司的这些抗凋亡作用。随后，依维莫司给药于肝IRI诱导小鼠提供了以下方面的肝保护作用：（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-α）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）恢复肝组织病理学。这些发现表明依维莫司通过激活自噬来保护肝脏免受肝脏IRI的影响，因此可能是肝脏IRI的潜在治疗剂。P.461
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 micewere utilized for the establishment of eachmodel. 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 antiapoptosis 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-a), (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. P.461