microRNA-223 promotes autophagy to aggravate lung ischemia-reperfusion injury by inhibiting the expression of transcription factor HIF2α.

Lung ischemia-reperfusion (I/R) injury severely endangers human health, and recent studies have suggested that certain microRNAs (miRNAs) play important roles in this pathological phenomenon. The current study aimed to ascertain the ability of miR-223 to influence lung I/R injury by targeting hypoxia-inducible factor-2 alpha (HIF2 alpha). First, mouse models of lung I/R injury were established: during surgical procedures, pulmonary arteries and veins and unilateral pulmonary portal vessels were blocked and resuming bilateral pulmonary ventilation, followed by restoration of bipulmonary ventilation. In addition, a lung I/R injury cell model was constructed by exposure to hypoxic reoxygenation (H/R) in mouse pulmonary microvascular endothelial cells (PMVECs). Expression of miR-223, HIF2 alpha, and beta-catenin in tissues or cells was determined by RT-qPCR and Western blot analysis. Correlation between miR-223 and HIF2 alpha was analyzed by dual luciferase reporter gene assay. Furthermore, lung tissue injury and mouse PMVEC apoptosis was evaluated by hematoxylin and eosin (H&E), TUNEL staining, and flow cytometry. Autophagosomes in cells were detected by light chain 3 immunofluorescence assay. miR-223 was expressed at a high level while HIF2 alpha/43-catenin was downregulated in tissues and cells with lung I/R injury. Furthermore, miR-223 targeted and repressed HIF2 alpha expression to downregulate beta-catenin expression. The miR-223/HIF2 alpha/beta-catenin axis aggravated H/R injury in mouse PMVECs and lung I/R injury in mice by enhancing autophagy. Taken together, miR-223 inhibits HIF2 alpha to repress beta-catenin, thus contributing to autophagy to complicate lung I/R injury. These findings provide a promising therapeutic target for treating lung I/R injury.