CircWDR33 alleviates human pulmonary microvascular endothelial cell injury in sepsis-associated acute lung injury by targeting miR-217-5p/SERP1 axis

Background: Circular RNAs (circRNAs) have been reported to be involved in the pathophysiology of sepsis -induced acute lung injury (sepsis-ALI). Herein, this work aimed to investigate the role and mechanism of circWDR33 in the process of sepsis-ALI.Methods: Lipopolysaccharide (LPS)-stimulated human pulmonary microvascular endothelial cells (HPMECs) were used to establish the cell model of sepsis-ALI in vitro. Levels of genes and proteins were measured by RT-qPCR and western blotting. The abundances of inflammatory factors were detected by ELISA analysis, and cell apoptosis was assayed by flow cytometry. Cell permeability (PA) was determined by transendothelial resistance (TER) and fluorescein isothiocyanate (FITC) with transwell assay. The tubulogenesis of HPMECs was assessed by tube formation assay. The binding between miR-217-5p and circWDR33 or SERP1 (Stress Associated Endo -plasmic Reticulum Protein 1) was validated using pull-down and dual-luciferase reporter assays.Results: CircWDR33 expression was low in sepsis-ALI patients and LPS-challenged HPMECs. Functionally, forced expression of circWDR33 could alleviate LPS-induced inflammatory and apoptotic injury, permeability enhancement and tubule formation arrest in HPMECs. Mechanistically, circWDR33/miR-217-5p/SERP1 formed an axis in HPMECs. MiR-217-5p was highly expressed, while SERP1 was decreased in sepsis-ALI patients and LPS-challenged HPMECs. MiR-217-5p silencing could protect against LPS-evoked HPMEC injury. Further rescue experiments showed that protective effects of circWDR33 on LPS-challenged HPMECs were attenuated by miR-217-5p up-regulation or SERP1 down-regulation.Conclusion: CircWDR33 protected against LPS-induced inflammatory and apoptotic injury, permeability enhancement and tubule formation arrest in HPMECs via miR-217-5p/SERP1 axis, indicating a new potential therapeutic approach for sepsis-ALI patients.

Automated summary

This study found that circular RNA circWDR33 plays a protective role in pulmonary microvascular endothelial cells by regulating the miR-217-5p/SERP1 axis, preventing inflammatory and apoptotic injury, permeability enhancement, and tubule formation arrest in sepsis-induced acute lung injury.