Circular RNAs: Functions and Clinical Significance in Cardiovascular Disease

Abstract

Cardiovascular disease (CVD) causes high morbidity and mortality worldwide. Accumulating research has indicated the possible roles played by circular RNAs (circRNAs) in the pathogenesis of CVD. CircRNAs are non-coding RNAs with covalently closed loop structures. CircRNAs can function by acting as miRNA sponges, RNA binding protein sponges, mRNA transcriptional regulators and templates for protein translation. The specific characteristics of circRNAs such as high stability, abundant distribution, and tissue- and developmental stage-specific expression make them potential biomarkers for the diagnosis and prognosis of CVD. In this paper, we systematically summarized the current knowledge regarding the biogenesis, biological properties and the action mechanisms of circRNAs, elucidated the roles played by circRNAs in the pathogenesis of CVD, and explored the diagnostic potential of circRNAs in CVD. With in-depth studies, an increasing number of molecular mechanisms underlying the participation of circRNAs in CVD may be elucidated, and the application of circRNAs in the clinical diagnosis and prevention of CVD may eventually be realized.

Keywords: cardiovascular disease; circular RNAs; clinical application; diagnosis; pathogenesis.

FIGURE 1

Biogenesis models of circRNAs. (A) Lariat-driven circularization model. The 5′ end of the intron (splice donor site, GU) and the 3′ end of the intron (splice acceptor site, AG) are covalently bound to generate an exon-containing lariat (one or more exons) which is internally spliced to form EcRNA. (B) Intron-pairing-driven circularization model. The RNA base motifs (e.g., Alu repeats) in the introns of pre-mRNA pair with the complementary sequences and the direct cyclization happens to generate ecRNAs or exon–intron circRNAs (EIciRNAs). (C) Circular intronic RNA (ciRNA) formation. The intron lariat is produced by backsplicing process. C-rich element close to the branch and the GU-rich element near the 5′ splice site bind together. The other exons and introns are removed by the spliceosome. (D) RNA binding protein (RBP)-driven model. The bridging of RBPs with pre-mRNAs can give rise to the production of circRNAs (ecRNAs or EIciRNAs).

FIGURE 2

Underlying action mechanisms of circRNAs and the circRNAs relevant to CVD pathogenesis. (A) CircRNAs can serve as miRNA sponges to regulate the functions of miRNAs. (B) CircRNAs can bind to RNA binding proteins (RBPs) to influence their functions. (C) CircRNAs can be the templates to encode proteins with the help of internal ribosome entry site (IRES) elements or m⁶A-modification (brown pin). (D) circRNAs with intronic sequences can regulate the expression of parental genes through binding to RNA polymerase II (Pol II). The circRNAs involved in CVD are listed in the blue box. The possible diagnostic biomarkers are displayed in the pink box. EcRNA, exonic circRNA; EIciRNA, exon–intron circRNA; CiRNA, circular intronic RNA.