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  • Review Article
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Non-canonical features of microRNAs: paradigms emerging from cardiovascular disease

Nature Reviews Cardiology volume 19, pages 620–638 (2022)Cite this article

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A Publisher Correction to this article was published on 30 May 2022

This article has been updated

Abstract

Research showing that microRNAs (miRNAs) are versatile regulators of gene expression has instigated tremendous interest in cardiovascular research. The overwhelming majority of studies are predicated on the dogmatic notion that miRNAs regulate the expression of specific target mRNAs by inhibiting mRNA translation or promoting mRNA decay in the RNA-induced silencing complex (RISC). These efforts mostly identified and dissected contributions of multiple regulatory networks of miRNA–target mRNAs to cardiovascular pathogenesis. However, evidence from studies in the past decade indicates that miRNAs also operate beyond this canonical paradigm, featuring non-conventional regulatory functions and cellular localizations that have a pathophysiological role in cardiovascular disease. In this Review, we highlight the functional relevance of atypical miRNA biogenesis and localization as well as RISC heterogeneity. Moreover, we delineate remarkable non-canonical examples of miRNA functionality, including direct interactions with proteins beyond the Argonaute family and their role in transcriptional regulation in the nucleus and in mitochondria. We scrutinize the relevance of non-conventional biogenesis and non-canonical functions of miRNAs in cardiovascular homeostasis and pathology, and contextualize how uncovering these non-conventional properties can expand the scope of translational research in the cardiovascular field and beyond.

Key points

  • MicroRNAs (miRNAs) are non-coding RNAs that mediate post-transcriptional repression of gene expression by pairing and loading target transcripts in RNA-induced silencing complexes, profoundly regulating cardiovascular development, physiology and disease progression.

  • The canonical biogenesis of miRNAs, involving transcription of canonical miRNA genes and two cleavage steps by the microprocessor complex and Dicer, can be bypassed by certain miRNAs that have relevant cardiovascular effects.

  • Non-canonical biogenesis involves alternative sources of precursors, miRNA duplexes with double functional strands for synergistic effects, miRNA isoforms with distinct targeting specificity after ischaemia, or even translation into small peptides.

  • In addition to RNA-induced silencing in the cytoplasm, miRNAs affect gene expression by regulating transcription and the epigenetic status of gene promoters and enhancers in the nucleus, and by targeting mitochondrially encoded transcripts.

  • miRNAs can directly affect protein functions by direct biophysical interactions, ultimately modulating crucial aspects of cardiovascular biology, such as endothelial integrity (miR-126-5p by inhibiting caspase 3) or cardiac action potential (miR-1-3p by binding to Kir2.1).

  • Extracellular miRNAs can mediate intercellular communication by silencing targets or interacting with cellular receptors, such as Toll-like receptors, in recipient cells, and the levels of extracellular miRNAs can be altered in cardiovascular diseases.

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Fig. 1: Atypical biogenesis of miRNAs implicated in cardiovascular diseases.
Fig. 2: Aptamer function of cardiovascular-relevant miRNAs.
Fig. 3: Non-conventional miRNA functions.

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Acknowledgements

The work of the authors is supported by the Deutsche Forschungsgemeinschaft (DFG; nos. 403584255 — TRR 267-A2 and SFB1123-A1/A10 to C.W.) and by the European Research Council (ERC; AdG 692511 to C.W.). C.W. is a Van de Laar professor of atherosclerosis.

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  1. Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität (LMU), Munich, Germany

    Donato Santovito & Christian Weber

  2. German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany

    Donato Santovito & Christian Weber

  3. Institute for Genetic and Biomedical Research (IRGB), Unit of Milan, National Research Council, Milan, Italy

    Donato Santovito

  4. Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, Netherlands

    Christian Weber

  5. Munich Cluster for Systems Neurology (SyNergy), Munich, Germany

    Christian Weber

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Santovito, D., Weber, C. Non-canonical features of microRNAs: paradigms emerging from cardiovascular disease. Nat Rev Cardiol 19, 620–638 (2022). https://doi.org/10.1038/s41569-022-00680-2

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