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miR-210 Participates in Hepatic Ischemia Reperfusion Injury by Forming a Negative Feedback Loop With SMAD4
Wen-Ming Pan1, Hui Wang1,2, Xiao-Fei Zhang3
1Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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.
Insights
MicroRNA-210 (miR-210) exacerbates liver injury by suppressing SMAD4 during hepatic ischemia-reperfusion (IR). Inhibiting miR-210 protects liver cells from damage, offering a potential therapeutic strategy for IR injury.
Area of Science:
- Hepatology
- Molecular Biology
- Cellular Biology
Background:
- Hepatic ischemia-reperfusion (IR) injury is a critical complication in liver transplantation and surgery.
- Hypoxia is a primary pathological event driving IR injury.
- The role of microRNA-210 (miR-210) in hepatic IR injury remains unclear.
Purpose of the Study:
- To investigate the function and mechanism of miR-210 in hepatic IR injury.
- To elucidate the interaction between miR-210 and SMAD4 in liver cells.
- To explore therapeutic potential for liver IR injury.
Main Methods:
- Analysis of miR-210 levels in human liver tissues and a murine IR model.
- In vitro studies using primary hepatocytes and LO2 cells to assess apoptosis.
- Investigation of the miR-210 and SMAD4 regulatory axis via 3' UTR binding and promoter analysis.
Main Results:
- miR-210 expression is induced in hepatic IR and promotes hepatocyte apoptosis.
- miR-210 directly suppresses SMAD4 expression, contributing to cell death.
- A negative feedback loop exists where hypoxia-induced SMAD4 upregulates miR-210.
Conclusions:
- The miR-210-SMAD4 interaction plays a key role in hepatic IR-induced cell death.
- Targeting miR-210 presents a promising therapeutic avenue for liver IR injury.
- Understanding this pathway could lead to novel treatment strategies.
