Involvement of circRNAs in the Development of Heart Failure

Abstract

In recent years, interest in non-coding RNAs as important physiological regulators has grown significantly. Their participation in the pathophysiology of cardiovascular diseases is extremely important. Circular RNA (circRNA) has been shown to be important in the development of heart failure. CircRNA is a closed circular structure of non-coding RNA fragments. They are formed in the nucleus, from where they are transported to the cytoplasm in a still unclear mechanism. They are mainly located in the cytoplasm or contained in exosomes. CircRNA expression varies according to the type of tissue. In the brain, almost 12% of genes produce circRNA, while in the heart it is only 9%. Recent studies indicate a key role of circRNA in cardiomyocyte hypertrophy, fibrosis, autophagy and apoptosis. CircRNAs act mainly by interacting with miRNAs through a "sponge effect" mechanism. The involvement of circRNA in the development of heart failure leads to the suggestion that they may be promising biomarkers and useful targets in the treatment of cardiovascular diseases. In this review, we will provide a brief introduction to circRNA and up-to-date understanding of their role in the mechanisms leading to the development of heart failure.

Keywords: cardiac fibrosis; cardiac hypertrophy; circRNA; heart failure; miRNA sponge.

Figure 1

Biogenesis of circRNA. The spliceosome mechanism that normally catalyzes the linear splicing of pre-mRNA s can also perform a back-splicing reaction between two exons, resulting in the formation of circRNA. Back-splicing uses the same canonical splicing machines and canonical splicing sites that are needed for linear splicing. Mechanically, backsplicing requires that the donor and acceptor sites of backspliced exons are in close proximity to each other. This can be achieved by direct pairing of RNA bases of inversely complementary sequences in the introns flanking the backspliced exons which bind to these flanking introns.

Figure 2

Different types of circular RNAs.

Figure 3

Functions of circular RNAs. (a) Ribosome. In the presence of internal ribosomal enter sites and a corresponding open reading frame, circRNAs can affect protein translation. (b) miRNA. CircRNAs can sponge the miRNAs to act as a cytoplasmic miRNA inventory. The scavenging of miRNAs removes the repression of target RNAs leading to an increase in their translation (in the case of mRNA) or activity (in case of lncRNA). (c) Protein. CircRNAs can act as a sponge for cytoplasmic proteins, retain certain transcription factors in the cytoplasm, or serve as a carrier for the transport of these molecules. (d) Substrate. CircRNAs can act as a scaffold for enzymes leading them to specific locations.