Dexmedetomidine alleviates pulmonary ischemia-reperfusion injury through modulating the miR-21-5p/Nr4a1 signaling pathway

Acta Biochim Pol. 2020 Dec 17;67(4):521-529. doi: 10.18388/abp.2020_5374.


This study aims to investigate the protection of dexmedetomidine (Dex) against pulmonary ischemia-reperfusion injury (PIRI) in the mouse model and reveal the mechanism in hypoxia reoxygenation (H/R)-induced mouse pulmonary vascular endothelial cells (MPVECs). The lung wet-to-dry weight ratio, histopathological features, and malondialdehyde (MDA) concentrations were measured. The H/R-induced MPVECs were exposed to Dex, and the cell viability, cell apoptosis and protein expressions were assessed by the Cell Counting Kit-8 (CCK8) assay, flow cytometry and western blot, respectively. In addition, the regulatory relationship between miR-21-5p and orphan nuclear receptor 4A1 (Nr4a1) was revealed by several assays, including the dual-luciferase reporter assay, real-time quantitative polymerase chain reaction (RT-qPCR) and western blot. We found that the Dex treatment significantly alleviated pulmonary injury and decreased the level of MDA and wet/dry weight ratio in PIRI mice. Dex treatment also increased cell viability, reduced apoptotic ratio and downregulated expression levels of Cleaved Caspase-3 and Cleaved Caspase-9 in H/R induced MPVECs. Furthermore, the expression of miR-21-5p was upregulated, while Nr4a1 was downregulated by Dex in a concentration-dependent manner in H/R induced MPVECs. Moreover, Nr4a1 was verified as a target of miR-497-5p. Overexpression of Nr4a1 could reverse the protective effects of Dex on alleviating H/R-induced injury in MPVECs. Taken together, Dex treatment attenuated ischemia-reperfusion induced pulmonary injury through modulating the miR-21-5p/Nr4a1 signaling pathway.

MeSH terms

  • Adrenergic alpha-2 Receptor Agonists / pharmacology*
  • Animals
  • Apoptosis / drug effects
  • Base Pairing
  • Base Sequence
  • Caspase 3 / genetics
  • Caspase 3 / metabolism
  • Caspase 9 / genetics
  • Caspase 9 / metabolism
  • Cell Survival / drug effects
  • Dexmedetomidine / pharmacology*
  • Endothelial Cells / drug effects*
  • Endothelial Cells / metabolism
  • Endothelial Cells / pathology
  • Female
  • Gene Expression Regulation
  • HEK293 Cells
  • Humans
  • Lung / drug effects
  • Lung / metabolism
  • Lung / pathology
  • Malondialdehyde / antagonists & inhibitors
  • Malondialdehyde / metabolism
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Nuclear Receptor Subfamily 4, Group A, Member 1 / antagonists & inhibitors
  • Nuclear Receptor Subfamily 4, Group A, Member 1 / genetics*
  • Nuclear Receptor Subfamily 4, Group A, Member 1 / metabolism
  • Reperfusion Injury / drug therapy*
  • Reperfusion Injury / genetics
  • Reperfusion Injury / metabolism
  • Reperfusion Injury / pathology
  • Signal Transduction


  • Adrenergic alpha-2 Receptor Agonists
  • MIRN-21 microRNA, mouse
  • MicroRNAs
  • Nr4a1 protein, mouse
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • Malondialdehyde
  • Dexmedetomidine
  • Casp3 protein, mouse
  • Casp9 protein, mouse
  • Caspase 3
  • Caspase 9