miR-210 Participates in Hepatic Ischemia Reperfusion Injury by Forming a Negative Feedback Loop With SMAD4.
miR-210 Participates in Hepatic Ischemia Reperfusion Injury by Forming a Negative Feedback Loop With SMAD4.
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miR-210 通过与 SMAD4 形成负反馈环参与肝缺血再灌注损伤
DOI：
10.1002/hep.31221
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发表时间：
2020-12
期刊：
影响因子：
--
通讯作者：
Zhang JX
中科院分区：
文献类型：
--
作者：
Pan WM;Wang H;Zhang XF;Xu P;Wang GL;Li YJ;Huang KP;Zhang YW;Zhao H;Du RL;Huang H;Zhang XD;Zhang JX
肝脏缺血再灌注（IR）损伤是肝移植、切除和失血性休克的主要并发症。缺氧是与IR损伤相关的关键病理事件。MicroRNA-210（miR-210）是缺氧通路的微观管理者。但其在肝脏IR损伤中的作用及机制尚不清楚。在这项研究中，我们发现miR-210在接受IR相关手术的患者的肝组织中被诱导。在肝脏IR的小鼠模型中，miR-210的水平在肝细胞中增加，但在非实质细胞中未增加。在小鼠肝脏IR模型中，miR-210缺陷显著减轻了肝损伤、细胞炎症反应和细胞死亡。在体外，抑制miR-210可以减少缺氧/复氧（HR）诱导的原代肝细胞和LO 2细胞的细胞凋亡，而过表达miR-210则会增加HR期间的细胞凋亡。从机制上讲，miR-210通过直接结合到正常和缺氧条件下的母亲十脊髓麻痹同源物4（SMAD 4）的3 'UTR，直接抑制其表达。SMAD 4减轻了miR-210的促凋亡作用，而短发夹SMAD 4消除了原代肝细胞中miR-210抑制的抗凋亡作用。进一步的研究表明，缺氧诱导SMAD 4进入细胞核，其中SMAD 4直接与miR-210的启动子结合并转录诱导miR-210，从而与miR-210形成负反馈环。我们的研究暗示了miR-210-SMAD 4相互作用在肝脏IR诱导的细胞死亡中的关键作用，并为肝脏IR损伤提供了一种有希望的治疗方法。
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. 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. 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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