Circular RNAs in Cardiac Regeneration: Cardiac Cell Proliferation, Differentiation, Survival, and Reprogramming

Abstract

Circular RNAs (circRNAs) are classified as long non-coding RNAs (lncRNAs) that are characterized by a covalent closed-loop structure. This closed-loop shape is the result of a backsplicing event in which the 3' and 5' splice sites are ligated. Through the lack of 3' poly(A) tails and 5' cap structures, circRNAs are more stable than linear RNAs because these adjustments make the circular loop less susceptible to exonucleases. The majority of identified circRNAs possess cell-and tissue-specific expression patterns. In addition, high-throughput RNA-sequencing combined with novel bioinformatics algorithms revealed that circRNA sequences are often conserved across different species suggesting a positive evolutionary pressure. Implicated as regulators of protein turnover, micro RNA (miRNA) sponges, or broad effectors in cell differentiation, proliferation, and senescence, research of circRNA has increased in recent years. Particularly in cardiovascular research, circRNArelated discoveries have opened the door for the development of potential diagnostic and therapeutic tools. Increasing evidence links deviating circRNA expression patterns to various cardiovascular diseases including ischemic heart failure. In this mini-review, we summarize the current state of knowledge on circRNAs in cardiac regeneration with a focus on cardiac cell proliferation, differentiation, cardiomyocyte survival, and cardiac reprogramming.

Alternative Splicing in Cardiovascular Disease—A Survey of Recent Findings

“…Circular RNAs (circRNAs), are covalently closed-loop RNA molecules formed through the ligation of a downstream donor site with an upstream splice acceptor site. [ 72 ] Their early discovery was followed by a stagnant phase where it was largely assumed that they had little functional significance, which lead to them being left largely unexplored in the ensuing decades [ 72 ]. Advances in high-throughput sequencing revealed their relative abundance and conservation across species, which lead to a renewed interest in the field [ 72 ].…”

“…[ 72 ] Their early discovery was followed by a stagnant phase where it was largely assumed that they had little functional significance, which lead to them being left largely unexplored in the ensuing decades [ 72 ]. Advances in high-throughput sequencing revealed their relative abundance and conservation across species, which lead to a renewed interest in the field [ 72 ]. Some of the discoveries pertaining to the role of circRNAs in the setting of myocardial infarction are detailed in this section.…”

Non-coding RNAs in Cardiac Regeneration

“…Circular RNA (circRNA) is a special subclass of ncRNAs characterized by a covalently closed loop structure, lacking 3′ poly(A) tails and 5′ cap structures ( Mester-Tonczar et al, 2020 ). circRNAs are highly conserved across multiple speciesand participate in various biological processes of the cardiovascular system such as cardiomyocyte hypertrophy, cardiac regeneration and cardiac development, re, and apoptosis, which suggests that circRNAs may play a critical role in heart failure ( Abbas et al, 2020 ).…”

Expression profiling and functional analysis of circular RNAs in vitro model of intermittent hypoxia-induced liver injury

“…CircRNAs are reported to be involved in a variety of human diseases, such as cancer ( Wang et al, 2020a ), stroke ( Wang et al, 2020b ), cardiovascular disorders ( Wang et al, 2020c ; Mester-Tonczar et al, 2020 ), neurodegenerative diseases ( Kumar et al, 2017 ), renal diseases ( Wu et al, 2021 ), and liver diseases ( Ou et al, 2019 ). There is no study evaluating circRNAs alterations and potential role of circRNAs in OSA-related liver injury.…”