Non-coding RNAs: emerging players in cardiomyocyte proliferation and cardiac regeneration

Abstract

Soon after birth, the regenerative capacity of the mammalian heart is lost, cardiomyocytes withdraw from the cell cycle and demonstrate a minimal proliferation rate. Despite improved treatment and reperfusion strategies, the uncompensated cardiomyocyte loss during injury and disease results in cardiac remodeling and subsequent heart failure. The promising field of regenerative medicine aims to restore both the structure and function of damaged tissue through modulation of cellular processes and regulatory mechanisms involved in cardiac cell cycle arrest to boost cardiomyocyte proliferation. Non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) are functional RNA molecules with no protein-coding function that have been reported to engage in cardiac regeneration and repair. In this review, we summarize the current understanding of both the biological functions and molecular mechanisms of ncRNAs involved in cardiomyocyte proliferation. Furthermore, we discuss their impact on the structure and contractile function of the heart in health and disease and their application for therapeutic interventions.

Keywords: Cardiomyocyte proliferation; Heart regeneration; MicroRNAs; circRNAs; lncRNAs.

Fig. 1

miRNA mode of action. In most cases, miRNAs bind to a specific sequence at the 3′ UTR of their target mRNAs. This binding results in either translational repression or degradation of the respective mRNA target

Fig. 2

Hippo pathway mediates the activity of miRNAs inducing cardiomyocyte proliferation. a The active dephosphorylated form if YAP/TAZ localizes to the nucleus and associates with TEAD transcription factors to drive cell proliferation genes expression. b miR-199a-3p, miR-1825, miR-302d, miR-373 and miR-33b downregulate cofilin 2, which disassembles actin filaments. The resulting cytoskeletal rearrangement leads to YAP activation and nuclear localization. c When Hippo signaling is on, MST1/2 activate LATS1/2 kinases, which in turn phosphorylate and inactivate the downstream effectors YAP and TAZ. miR-302/367 complex directly targets the expression of MST1, LATS2 and MOB1B, thereby blocking the Hippo signaling. miR-1825 activates miR-199a-3p, resulting in the downregulation of its target genes TAOK1 and β-TrCP, eventually leading to Hippo pathway repression and prevention of YAP degradation. miR-31a-5p downregulates RhoBTB1 and results in Hippo deactivation

Fig. 3

lncRNA modes of action. (1) signal—acts in response to stimuli, (2) decoy—sequesters transcription factors/protein complex, (3) guide—guides transcription factors/protein complex to a specific target site, (4) scaffold—brings together multi-protein complexes, (5) enhancer—induces chromosomal looping to increase association between enhancer and promoter regions, and (6) sponge—acts as a competing endogenous RNA (ceRNA) and sponge miRNAs