Genome-wide characterization of circular RNAs in three rat models of pulmonary hypertension reveals distinct pathological patterns.

Abstract

Background: Pulmonary hypertension (PH) is a devastating disease marked by elevated pulmonary artery pressure, resulting in right ventricular (RV) failure and mortality. Despite the identification of several dysregulated genes in PH, the involvement of circular RNAs (circRNAs), a subset of long noncoding RNAs, remains largely unknown.

Methods: In this study, high-throughput RNA sequencing was performed to analyze the genome-wide expression patterns of circRNAs in pulmonary arteries from three models of PH rats induced by hypoxia (Hyp), hypoxia/Sugen5416 (HySu), and monocrotaline (MCT). Differentially expressed circRNAs (DEcircRNAs) were identified, and a weighted gene coexpression network was constructed to explore circRNA networks associated with PH pathogenesis. A circRNA-miRNA-mRNA regulatory network was built, and the functional significance of targeted mRNAs was evaluated. Single-cell RNA sequencing provided insights into the distribution of cell type-specific circRNAs across PH progression.

Results: Our analysis revealed 45 circRNAs exhibiting significant changes across all three PH rat models, with their host genes participating in the calcium signaling and muscle contraction. We identified 372 PH-related circRNA-miRNA-mRNA interactions, shedding light on the regulatory networks during PH development. Furthermore, we uncovered 186, 195 and 311 Hyp-, Hysu- and MCT-specific circRNAs, respectively. These circRNAs were enriched in distinct biological processes, emphasizing their unique regulatory roles. Single-cell spatial distribution analysis of these circRNAs in the pulmonary arteries of PH patients revealed that Hyp-specific circRNA predominantly appeared in the pulmonary vascular structural cells, while HySu- and MCT-specific circRNAs exhibited broader distribution, including significant enrichment in immune-related cells.

Conclusion: Our study presents the first comprehensive view of circRNA regulatory networks in the pulmonary arteries of three PH rat models. We provide insights into PH-associated circRNAs, particularly their involvement in calcium signaling and muscle contraction.