Integrated Analysis of Rat Pulmonary Hypertension Datasets Identifies Candidate circRNA Networks in Hypoxia-Exposed Pulmonary Artery Tissue.

Pulmonary hypertension (PH) is a progressive and life-threatening disease characterised by elevated pulmonary arterial pressure, vascular remodelling and right ventricular dysfunction. Emerging evidence implicates circular RNAs (circRNAs) in the regulation of vascular remodelling and inflammation; however, their contribution to PH remains poorly understood. Here, we performed an in silico analysis using a multi-tool circRNA discovery pipeline across three publicly available transcriptomic datasets derived from experimental rat models of PH: H_PRN (PRJNA809145; pulmonary artery tissue from normoxic and hypoxia-induced PH rats; 21% vs. 10% O2; n = 7), H_GSE (GSE159668; right lung tissue from normoxic and hypoxia-induced PH rats; 21% vs. 10% O2; n = 6) and M_PRN (PRJNA732522; total lung tissue from control and monocrotaline-induced PH rats; n = 6). CircRNAs were detected in all datasets; however, robust differentially expressed candidates were identified primarily in the hypoxia-exposed pulmonary artery dataset (H_PRN). In this dataset, three circRNAs-circCnot6l, circSmoc1 and circNtrk3-met the differential expression criteria (Benjamini-Hochberg adjusted p-value (FDR q) < 0.05, absolute log2 fold-change > 1). Downstream network analysis from unpaired samples prioritised circCnot6l and circNtrk3 as potential regulators of circRNA-microRNA (miRNA) and miRNA-messenger RNA axes involving miR-204-5p and miR-205, respectively. The predicted target networks were enriched for genes associated with key PH-related processes, including cell proliferation, adhesion, migration, angiogenesis and vascular development. Collectively, these findings identify circCnot6l and circNtrk3 as promising circRNA candidates involved in hypoxia-induced pulmonary artery remodelling and provide a foundation for future experimental studies investigating circRNA-mediated mechanisms underlying PH pathogenesis.