Introduction. Pulmonary hypertension (PH) is a prevalent form of hypertension that leads to heart failure. Recent research suggests that circular RNAs (circRNA), a form of circularized non-coding RNAs, function as post-transcription regulators by sponging micro RNAs (miRNA) and may contribute to PH pathogenesis. However, the identification of circRNAs as potential biomarkers in PH remains underexplored.
Aims. To identify circRNA-miRNA-gene pathways associated with PH pathogenesis.
Methods. We used a publicly available dataset (PRJNA809145) of pulmonary artery smooth muscle cells harvested from hypoxia induced adult, male Sprague-Dawley rats as a PH model and healthy controls. CircRNAs were identified and quantified using CIRI2, CIRIquant, circRNA_finder and find-circ. Differentially expressed circRNAs were identified using edgeR and multiomics analysis was conducted using mixOmics and a weighted gene co-expression network analysis (WGCNA). Finally, we used AmiGO2 to perform gene ontology and STRING to perform protein enrichment analyses.
Results. circCnot6l/miR-204-5p and circNtrk3/miR-205 axis were significantly differentially expressed (Log2FC>1, FDR<0.05) in the PH model. Moreover, all downstream targets (n=24) show significant gene intra-relation (module membership>0.8) and correlate with the phenotype of hypoxia induced pulmonary hypertension (HPH(r)>0.8). Particularly gene Angpt2, which plays a key role in vascular remodeling and inflammation.
Discussion. This study shows that circCnot6l and circNtrk3 are potentially involved in the development of PH and could serve as therapeutic targets. Future studies are needed to explore the roles of these circRNAs in human PH and evaluate their clinical relevance.