The role and mechanism of rosiglitazone in endothelial-to-mesenchymal transition in pulmonary hypertension
Abstract
Objective
Pulmonary hypertension (PH) involves endothelial-to-mesenchymal transition (EndMT) in vascular remodeling. Rosiglitazone (RSG), a peroxisome proliferator-activated receptor gamma agonist, alleviates PH, but its direct effect on EndMT is unclear. The study explores RSG's role and mechanism in inhibiting EndMT.
Materials and methods
A hypoxia-induced human pulmonary artery endothelial cells (HPAECs) model was used to evaluate proliferation, migration, and EndMT after RSG treatment. Gene overexpression, small interfering RNA-mediated knockdown, short hairpin RNA-mediated silencing, miRNA mimics and inhibitors were performed to investigate the urothelial carcinoma associated 1 (UCA1)/miR-206/protein kinase cyclic adenosine monophosphate-activated catalytic subunit beta (PRKACB) axis, combined with reverse transcription quantitative polymerase chain reaction, Western blot, and immunofluorescence. A monocrotaline-induced PH rat model was used for in vivo validation.
Results
Increased UCA1 and PRKACB expression and decreased miR-206 levels were observed under hypoxia. RSG treatment inhibited proliferation, migration, and EndMT in HPAECs and reversed these molecular changes. Functional assays showed that silencing UCA1 or PRKACB, or overexpressing miR-206, exerted a protective effect similar to that of RSG; miR-206 inhibition counteracted RSG effects. In vivo, RSG improved right ventricular function, reduced hypertrophy, and alleviated pulmonary vascular remodeling while restoring miR-206 and reducing PRKACB expression.
Conclusion
These findings reveal that RSG inhibits EndMT through regulating the noncoding RNA/PRKACB axis, suggesting that RSG can serve as a promising drug repurposing candidate for PH treatment.