Hypoxia-induced microRNA-191 contributes to hepatic ischemia/reperfusion injury through the ZONAB/Cyclin D1 axis
Hypoxia-induced microRNA-191 contributes to hepatic ischemia/reperfusion injury through the ZONAB/Cyclin D1 axis
复制标题
缺氧诱导的 microRNA-191 通过 ZONAB/Cyclin D1 轴导致肝缺血/再灌注损伤。
DOI：
10.1038/s41418-018-0120-9
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发表时间：
2019-02-01
影响因子：
12.4
通讯作者：
Wang, Hui
中科院分区：
文献类型：
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作者：
Pan, Wenming;Wang, Lin;Wang, Hui
肝缺血/再灌注损伤（IRI）是肝移植中发病率和死亡率的常见原因，并且涉及严重的细胞死亡和炎症反应。MicroRNA-191在肝细胞癌和其他肝脏疾病中异常表达，参与重要的细胞过程的调控。然而，其在IRI中的功能和分子机制尚不清楚。在这里，我们证明了miR-191在缺氧/再灌注（H/R）期间在培养的细胞系中以及在小鼠IRI期间在肝组织中显著上调。低氧条件下miR-191的激活是通过低氧诱导因子-1 α（HIF 1 α）与其启动子区域的结合介导的。通过CRISPR/Cas9系统构建了Global miR-191 KO小鼠，我们发现miR-191缺陷显著降低了小鼠肝脏IRI模型中的肝组织损伤、细胞炎症反应和细胞死亡。在缺氧/复氧条件下，miR-191过表达促进G 0/G1期细胞阻滞和细胞凋亡，而抑制miR-191则促进细胞周期进程，减少细胞死亡。从机制上讲，在缺氧或缺血诱导后，miR-191抑制ZO-1相关Y盒因子（ZONAB）及其下游因子Cyclin D1的表达，从而导致细胞死亡和组织损伤。此外，miR-191对细胞周期停滞和细胞凋亡的影响被ZONAB过表达所消除，反之亦然。综上所述，我们的结果表明HIF 1 α/miR-191/ZONAB信号通路在肝脏IRI中的重要作用，并表明miR-191是治疗肝脏IRI的新靶点。
Hepatic ischemia/reperfusion injury (IRI) is a common cause of morbidity and mortality in liver transplantation settings and involves severe cell death and inflammatory responses. MicroRNA-191 has recently been reported to be abnormally expressed in hepatocellular carcinoma and other liver diseases in the regulation of important cellular processes. However, little is known about its function and molecular mechanism in IRI. Here, we demonstrate that miR-191 is significantly upregulated in a cultured cell line during hypoxia/reperfusion (H/R) and in liver tissue during IRI in mice. The activation of miR-191 under hypoxic conditions is mediated by hypoxia-inducible factor-1α (HIF1α) binding to its promoter region. Global miR-191 KO mice were constructed by CRISPR/Cas9 system, and we found that miR-191 deficiency markedly reduces liver tissue damage, cell inflammatory responses and cell death in a mouse hepatic IRI model. Under the H/R condition, miR-191 overexpression promotes G0/G1 cell cycle arrest and cell apoptosis, but inhibition of miR-191 facilitates cell cycle progression and decreases cell death. Mechanistically, upon induction by hypoxia or ischemia, miR-191 suppresses expression of ZO-1-associated Y-box factor (ZONAB) and its downstream factor Cyclin D1, consequently resulting in cell death and tissue injury. Moreover, the effects of miR-191 on cell cycle arrest and cell apoptosis are abrogated by ZONAB overexpression, and vice versa. Taken together, our results indicate an important role of the HIF1α/miR-191/ZONAB signaling pathway in hepatic IRI and suggest miR-191 as a novel therapeutic target for the treatment of liver IRI.