2. Academic Validation
  3. MicroRNA let-7a mediates posttranscriptional inhibition of Nr4A1 and exacerbates cardiac allograft rejection

MicroRNA let-7a mediates posttranscriptional inhibition of Nr4A1 and exacerbates cardiac allograft rejection

  • Cell Signal. 2023 Jun 23;110783. doi: 10.1016/j.cellsig.2023.110783.
Xiangchao Ding 1,  Yifan Du 2,  Bing Sun 3,  Liang Liu 4,  Sheng Le 5,  Chuangyan Wu 6,  Jiuling Chen 6,  Xing Chen 7,  Shanshan Chen 8,  Jiahong Xia 9
Affiliations

Affiliations

  • 1 Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, China.
  • 2 Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 3 Wuhan Third Hospital (Tongren Hospital of Wuhan University), Wuhan, China.
  • 4 Department of Cardiovascular Surgery, Renmin Hospital of Wuhan University, Wuhan, China.
  • 5 Department of Thoracic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China.
  • 6 Departments of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 7 Department of Cardiovascular Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China.
  • 8 Key Laboratory for Molecular Diagnosis of Hubei Province and Central Laboratory, Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: shanshan_chen123@126.com.
  • 9 Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: jiahong.xia@hust.edu.cn.
PMID: 37356602 DOI: 10.1016/j.cellsig.2023.110783
Abstract

Background: Acute allograft rejection remains a major obstacle after heart transplantation, and CD4+ T cells play a crucial role in allograft rejection. Upregulation of Nr4A1 could regulate CD4+ T-cell function and alleviate allograft rejection. However, the regulatory mechanism of Nr4A1 in allograft rejection remains elusive.

Methods: BCLb/c mouse hearts were transplanted into WT C57BL/6 mice, and dynamic detection of the changes in Nr4A1 expression revealed that Nr4A1 was regulated posttranscriptionally after heart transplantation. Potential upstream miRNAs of Nr4A1 were screened, and the transfection of cells with these miRNA mimics/inhibitors and dual-luciferase reporter experiments were performed to clarify the regulatory mechanism of miRNAs on Nr4A1 expression. The miRNA agomiR/antagomiR was applied in vivo to validate the role of the corresponding miRNA in heart transplantation. Finally, Nr4A1 knockout mice and an adoptive T-cell cotransfer model were used to confirm the specific effects of miRNA.

Results: The expression of Nr4A1 protein (rather than mRNA) exhibited a trend of initially increasing and then decreasing rapidly, and this phenomenon could not be reversed by lysosomal or proteasomal inhibitors. The miRNA let-7a directly binds to the Nr4A1 3'UTR and posttranscriptionally regulates Nr4A1 expression. The let-7a antagomiR prolonged allograft survival and regulated CD4+ T-cell function by upregulating Nr4A1 protein expression in CD4+ T cells.

Conclusions: This study confirmed that let-7a is a potential target for interfering with Nr4A1 expression in CD4+ T cells and preventing the pathological progression of cardiac allograft rejection.

Keywords

CD4+ T cells; Heart transplantation; Let-7a; Nr4A1; Posttranscriptional regulation.

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