Decoding ceRNA Regulatory Network in Pulmonary Artery of Hypoxia-Induced Pulmonary Hypertension (HPH) Rat Model

Abstract

Background Hypoxia-induced pulmonary hypertension (HPH) is a lethal cardiovascular disease with the characteristic of severe remodelling of pulmonary vascular. Although large number of dysregulated mRNAs, lncRNAs, circRNAs and miRNAs related to HPH have been identified in extensive studies, the RNA regulatory network in pulmonary artery that respond to hypoxia remains poorly understood. Results Transcriptomic profiles in pulmonary arteries of HPH rats were interrogated through high-throughput RNA sequencing in this study. The differentially expressed RNAs (DERNAs) including DEmRNAs, DElncRNAs, DEcircRNAs and DEmiRNAs between HPH and normal rats were investigated. A set of 19 DEmRNAs, 8 DElncRNAs, 19 DEcircRNAs and 23 DEmiRNAs were identified through a relatively strict screening. The DEmRNAs were further found to be involved in cell adhesion, axon guidance, PPAR signalling pathway and calcium signalling pathway, suggesting their crucial role in HPH. Furthermore, according to the competitive endogenous RNA (ceRNA) hypothesis, a hypoxia induced ceRNA regulatory network in pulmonary arteries of HPH rats was constructed. More specifically, the ceRNA network was composed of 10 miRNAs as hub nodes, which might be sponged by 6 circRNAs and 7 lncRNAs, and directed the expression of 18 downstream target genes that might play important role in the progression of HPH. Expression pattern of selected DERNAs in the ceRNA network were validated to be in consistent with sequencing results. Diagnostic effectiveness of several hub mRNAs were further evaluated through investigating their expression profiles in patients with pulmonary artery hypertension (PAH) recorded in the Gene Expression Omnibus (GEO) dataset GSE117261. Dysregulated POSTN, LTBP2, SPP1 and LSAMP were observed in both the pulmonary arteries of HPH rats and lung tissues of PAH patients. Conclusions A ceRNA regulatory network in pulmonary arteries of HPH rats was constructed, 10 hub miRNAs and their corresponding interacting lncRNAs, circRNAs and mRNAs were identified. The expression pattern of selected DERNAs were further validated to be in consistent with sequencing result. POSTN, LTBP2, SPP1 and LSAMP were suggested to be potential diagnostic biomarkers and therapeutic targets for PAH.