Decoding ceRNA regulatory network in the 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 remodeling of pulmonary vascular. Although a large number of dysregulated mRNAs, lncRNAs, circRNAs, and miRNAs related to HPH have been identified from extensive studies, the competitive endogenous RNA (ceRNA) regulatory network in the pulmonary artery that responds to hypoxia remains largely unknown. Results Transcriptomic profiles in the pulmonary arteries of HPH rats were characterized through high-throughput RNA sequencing in this study. Through relatively strict screening, a set of differentially expressed RNAs (DERNAs) including 19 DEmRNAs, 8 DElncRNAs, 19 DEcircRNAs, and 23 DEmiRNAs were identified between HPH and normal rats. The DEmRNAs were further found to be involved in cell adhesion, axon guidance, PPAR signaling pathway, and calcium signaling pathway, suggesting their crucial role in HPH. Moreover, a hypoxia-induced ceRNA regulatory network in the pulmonary arteries of HPH rats was constructed according to the ceRNA hypothesis. 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. The expression patterns of selected DERNAs in the ceRNA network were then validated to be consistent with sequencing results in another three independent batches of HPH and normal control rats. The diagnostic effectiveness of several hub mRNAs in ceRNA network was 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 the pulmonary arteries of HPH rats was constructed, 10 hub miRNAs and their corresponding interacting lncRNAs, circRNAs, and mRNAs were identified. The expression patterns of selected DERNAs were further validated to be consistent with the sequencing result. POSTN, LTBP2, SPP1, and LSAMP were suggested to be potential diagnostic biomarkers and therapeutic targets for PAH.

Circ‐ZNF236 mediates stem cells from apical papilla differentiation by regulating LGR4‐induced autophagy

“…At present, in terms of mechanisms, circRNAs exert their function mainly through the following activities (Patop et al., 2019; Rong et al., 2022; Wang, Niu, et al., 2022): (a) serving as a competitive endogenous RNA (ceRNA) that is, circRNA absorbs miRNA in the cytoplasm to reduce the binding of miRNA to downstream target genes; (b) binding to related proteins in the cytoplasm; (c) acting as scaffolding proteins for protein–protein interactions and (d) combining with corresponding proteins in the nucleus, stabilizing them so that they are not easily degraded. In this study, circ‐ZNF236 and miR‐218‐5p were colocalized in the cytoplasm of SCAPs, as shown by nucleocytoplasmic separation and FISH assay results.…”

The gene expression of CALD1, CDH2, and POSTN in fibroblast are related to idiopathic pulmonary fibrosis

“…We hypothesize that this difference may be linked to posttranscriptional regulation, recognizing the inherent limitations in the cell model. In a study (48) involving hypoxia-induced pulmonary hypertension (HPH), miR205, miR-20a-5p, and miR-541 were predicted to target POSTN, and these microRNAs might compete with several lncRNAs and circRNAs for binding to POSTN. Whether POSTN exhibits certain post-transcriptional regulatory mechanisms in pulmonary fibrosis remains to be investigated.…”

Identification of hub genes based on integrated analysis of single-cell and microarray transcriptome in patients with pulmonary arterial hypertension

“…Nowadays, high-throughput RNA sequencing has been widely used to explore novel mechanisms of PAH [ 6 , 43 ]. Especially, with the rapid development of single-cell sequencing, integrated bioinformatics analysis of microarray transcriptome and scRNA-seq, a newly-rising research method, has attracted researchers’ attention lately [ 44 ].…”