Dataset Information

MiR-210 Participates in Hepatic Ischemia Reperfusion Injury by Forming a Negative Feedback Loop With SMAD4.

ABSTRACT:

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.

SUBMITTER: Pan WM

PROVIDER: S-EPMC7818437 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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miR-210 Participates in Hepatic Ischemia Reperfusion Injury by Forming a Negative Feedback Loop With SMAD4.

Pan Wen-Ming WM Wang Hui H Zhang Xiao-Fei XF Xu Peng P Wang Guo-Liang GL Li Yi-Jing YJ Huang Kun-Peng KP Zhang Yun-Wei YW Zhao Huan H Du Run-Lei RL Huang Hai H Zhang Xiao-Dong XD Zhang Jin-Xiang JX

Hepatology (Baltimore, Md.) 20200902 6

<h4>Background and aims</h4>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.<h4>Approach and results</h4>In this study, we found miR-210 was induced in liver tissues from patients subjected to IR-related surg ...[more]

PMID: 32155285

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