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

Abstract

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.

• Authors: Wei Dong, Hongxia Yang, Minghua Cheng, Xin Zhang, Jingjing Yin, Zhaodong Zeng, Guang Huang
• Journal: Acta biochimica Polonica (Acta Biochim Pol) Vol. 67 Issue 4 Pg. 521-529 (Dec 17 2020) ISSN: 1734-154X [Electronic] Poland
• PMID: 33332077 (Publication Type: Journal Article)

Chemical References

• 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

Topics

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