Abstract

Background Circular RNAs (circRNAs) function as important modulators in the progression of pulmonary arterial hypertension (PAH). Here, we aimed to discover the role and working mechanism of circATP2B4 in hypoxia-induced proliferation and migration of PASMCs. Methods The proliferation, migration and apoptosis of pulmonary arterial smooth muscle cells (PASMCs) were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), wound healing assay and flow cytometry. The expression of circATP2B4, ATPase plasma membrane Ca 2+ transporting 4 (ATP2B4), microRNA-223 (miR-223) and ATR serine/threonine kinase (ATR) was quantified by quantitative real time polymerase chain reaction (qRT-PCR). Circular RNA Interactome and microT-CDS were used to search the targets of circATP2B4 and miR-223, respectively. Dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were used to validate the above predictions. Western blot assay was performed to detect the protein expression of ATR. Results Hypoxia treatment promoted the proliferation and migration and impeded the apoptosis of PASMCs. A significant increase of circATP2B4 expression was observed in the serum of PAH patients and hypoxia-induced PASMCs compared with healthy volunteers and PASMCs under normoxia condition. MiR-223 is a target of circATP2B4, and the effects of circATP2B4 silencing on PASMCs were overturned by the transfection of anti-miR-223. ATR is a functional target of miR-223, and miR-223 inhibited the proliferation and migration while accelerated the apoptosis of PASMCs through targeting and down-regulating ATR. CircATP2B4 could up-regulate the level of ATR through sponging miR-223 in PSAMCs. Conclusion CircATP2B4 potentiated hypoxia-induced proliferation and migration of PASMCs through the miR-223/ATR axis. Restoration of the level of miR-223 might be an effective therapeutic method for the treatment of PAH.