Circ-OSBPL2 Contributes to Smoke-Related Chronic Obstructive Pulmonary Disease by Targeting miR-193a-5p/BRD4 Axis

Abstract

Background Circular RNAs (circRNAs) have been identified to play roles in the respiratory diseases. Here, this study aimed to elucidate the function of circRNA oxysterol binding protein like 2 (circOSBPL2) in the development of smoke-related chronic obstructive pulmonary diseases (COPD). Methods The expression of circ-OSBPL2, microRNA (miR)-193a-5p, and bromodomain-containing protein 4 (BRD4) was detected using qRT-PCR and Western blot assays. Cigarette smoke extract (CSE)-induced human bronchial epithelial cells (HBECs) was applied to mimic smoke-related COPD in vitro. Flow cytometric analysis of cell apoptosis and ELISA analysis of interleukins (IL)-6, IL-8, tumor necrosis factor-α (TNF-α) levels were performed. The malondialdehyde (MDA) and superoxide dismutase (SOD) production levels were analyzed according to the kit instructions. The binding interaction between miR-193a-5p and circ-OSBPL2 or BRD4 was confirmed by dual-luciferase reporter assay and RNA immunoprecipitation assays. Results Circ-OSBPL2 was highly expressed in lung tissues of smokers without or with COPD, particularly in smokers with COPD. Also, the expression of circ-OSBPL2 was dose and time-dependently elevated in CSE-induced HBECs. Circ-OSBPL2 down-regulation in HBECs attenuated CSE-evoked cell proliferation arrest, and cell apoptosis, inflammation and oxidative stress promotion. Mechanistically, circ-OSBPL2 served as a sponge for miR-193a-5p, and miR-193a-5p inhibition reversed the effects of circ-OSBPL2 knockdown on CSE-mediated HBECs. Besides that, miR-193a-5p directly targeted BRD4, and miR-193a-5p re-expression in HBECs abolished CSE-induced HBEC injury, which was reverted by BRD4 up-regulation. Additionally, we also found circ-OSBPL2 could indirectly regulate BRD4 via miR-193a-5p. Conclusion Circ-OSBPL2 contributed to the apoptosis, inflammation, and oxidative stress of HBECs in smoke-related COPD by miR-193a-5p/BRD4 axis, suggesting a novel insight on the pathogenesis of COPD and a potential therapeutic strategy for future clinic intervention in COPD.