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Pan, Wen‐Ming; Wang, Hui; Zhang, Xiao‐Fei; Xu, Peng; Wang, Guo‐Liang; Li, Yi‐Jing; Huang, Kun‐Peng; Zhang, Yun‐Wei; Zhao, Huan; Du, Run‐Lei; Huang, Hai; Zhang, Xiao‐Dong; Zhang, Jin‐Xiang
Hepatology, December 2020, Volume: 72, Issue: 6Journal Article
Background and Aims Hepatic ischemia‐reperfusion (IR) injury is a major complication of liver transplantation, resection, and hemorrhagic shock. Hypoxia is a key pathological event associated with IR injury. MicroRNA‐210 (miR‐210) has been characterized as a micromanager of hypoxia pathway. However, its function and mechanism in hepatic IR injury is unknown. Approach and Results In this study, we found miR‐210 was induced in liver tissues from patients subjected to IR‐related surgeries. In a murine model of hepatic IR, the level of miR‐210 was increased in hepatocytes but not in nonparenchymal cells. miR‐210 deficiency remarkably alleviated liver injury, cell inflammatory responses, and cell death in a mouse hepatic IR model. In vitro, inhibition of miR‐210 decreased hypoxia/reoxygenation (HR)–induced cell apoptosis of primary hepatocytes and LO2 cells, whereas overexpression of miR‐210 increased cells apoptosis during HR. Mechanistically, miR‐210 directly suppressed mothers against decapentaplegic homolog 4 (SMAD4) expression under normoxia and hypoxia condition by directly binding to the 3′ UTR of SMAD4. The pro‐apoptotic effect of miR‐210 was alleviated by SMAD4, whereas short hairpin SMAD4 abrogated the anti‐apoptotic role of miR‐210 inhibition in primary hepatocytes. Further studies demonstrated that hypoxia‐induced SMAD4 transported into nucleus, in which SMAD4 directly bound to the promoter of miR‐210 and transcriptionally induced miR‐210, thus forming a negative feedback loop with miR‐210. Conclusions Our study implicates a crucial role of miR‐210‐SMAD4 interaction in hepatic IR‐induced cell death and provides a promising therapeutic approach for liver IR injury.
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