Circular RNAs in pulmonary hypertension: Emerging biological concepts and potential mechanism

Abstract

Circular RNAs (circRNAs) are endogenous RNAs with a covalently closed single-stranded transcript. They are a novel class of genomic regulators that are linked to many important development and disease processes and are being pursued as clinical and therapeutic targets. Using the most powerful RNA sequencing and bioinformatics techniques, a large number of circRNAs have been identified and further functional studies have been performed. It is known that circRNAs act as potential biomarkers, sponges for microRNAs (miRNAs) and RNA-binding proteins (RBPs), and regulators of mRNA transcription. They also participate in the translation of peptides or proteins. Many types of circRNAs are dysregulated in plasma or lung tissues, and they may be involved in regulating the proliferation and apoptosis of pulmonary artery endothelial cells (PAECs) and pulmonary artery smooth muscle cells (PASMCs), leading to pulmonary vascular remodeling in pulmonary hypertension (PH). One possible mechanism is that circRNAs can regulate the function of PAECs and PASMCs by acting as miRNA sponge. However, other potential mechanisms of action of circRNAs are still being actively explored in PH. This paper presents a systematic review of the biogenesis, biological characterization, relevant underlying functions, and future perspectives for studies of circRNAs in the pathogenesis of PH.

Keywords: biological characterization; circular RNAs; miRNA sponges; pulmonary hypertension.

FIGURE 1

History of the discovery and development of circRNAs, , , , , , , , , , , , , , , , , , , , , , , , , ,

FIGURE 2

The classification, formation mechanism, degradation, and functions of circRNAs. (A) The classification and formation mechanism of circRNA biogenesis. Intron pairing–driven circularization: The intron motifs on both sides of the cyclization region show reverse complementarity, which could enable the two exons to form a loop of EcircRNA after removing or retaining certain introns. RBP/trans‐factor‐dependent cyclization: RBPs bridge two flanking introns close together and then remove introns to form ecircRNA or ElcircRNA. Lariat‐driven circularization: The 3′ splice donor of exon 1 and the 5′ splice acceptor of exon 4 link up end‐to‐end by exon skipping and form an exon‐containing lariat structure; after the removal of introns, ecircRNA or ciRNA is formed. Variable cyclization: Splicing selection and exon circularization may be influenced by inverted repeated ALU pairs (IRAlus) and the competition between them. (B) The functions of circRNAs. Regulation transcription: CircRNAs regulate the transcription of their parent coding genes. Protein translation: CircRNAs have a coding potential and can be translated into proteins with ribosomes. Interaction with RBPs: CircRNAs can bind to RBPs to regulate mRNA expression by altering the splicing pattern or mRNA stability. Acting as miRNA sponges: CircRNAs contain a common miRNA response element that can bind to miRNA and prevent them from interacting with mRNA. (C) The degradation of circRNAs. UPF1 and G3BP1 can bind to imperfect base‐paired regions of circRNAs and induce their degradation. Upon viral infection, RNase L activated by 2′‐5′‐oligoadenosine(2′‐5′A) causes complete degradation of circRNAs, thereby relieving PKR suppression. m⁶A ‐containing circRNAs can be recognized by YTHDF2, which interacts with the RNase P/motility‐related protein (MRP) complex bridged by HRSP12, and then the complex endoribonucleolytically cleaves circRNAs

FIGURE 3

Summary of the studies of circRNAs in PH