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  • Review Article
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Non-coding RNAs as therapeutic targets and biomarkers in ischaemic heart disease

Abstract

The adult heart is a complex, multicellular organ that is subjected to a series of regulatory stimuli and circuits and has poor reparative potential. Despite progress in our understanding of disease mechanisms and in the quality of health care, ischaemic heart disease remains the leading cause of death globally, owing to adverse cardiac remodelling, leading to ischaemic cardiomyopathy and heart failure. Therapeutic targets are urgently required for the protection and repair of the ischaemic heart. Moreover, personalized clinical biomarkers are necessary for clinical diagnosis, medical management and to inform the individual response to treatment. Non-coding RNAs (ncRNAs) deeply influence cardiovascular functions and contribute to communication between cells in the cardiac microenvironment and between the heart and other organs. As such, ncRNAs are candidates for translation into clinical practice. However, ncRNA biology has not yet been completely deciphered, given that classes and modes of action have emerged only in the past 5 years. In this Review, we discuss the latest discoveries from basic research on ncRNAs and highlight both the clinical value and the challenges underscoring the translation of these molecules as biomarkers and therapeutic regulators of the processes contributing to the initiation, progression and potentially the prevention or resolution of ischaemic heart disease and heart failure.

Key points

  • Ischaemic heart disease causes adverse cardiac remodelling, leading to ischaemic cardiomyopathy and heart failure, and is the leading cause of death globally.

  • Non-coding RNAs (ncRNAs) are functional RNA molecules that are not translated into proteins; these molecules are involved in cardiovascular homeostasis and the regulation of mechanisms that lead to ischaemic heart disease.

  • ncRNAs are being investigated for their capacity to combat ischaemic cardiac remodelling, promote therapeutic angiogenesis and replace cardiomyocyte loss, and as biomarkers of cardiac injury and remodelling.

  • The various classes of ncRNA interact among themselves and with mRNAs and RNA-binding proteins, establishing complex regulatory networks; post-transcriptional modifications expand the therapeutic target repertoire of ncRNAs.

  • ncRNAs are released extracellularly and circulate in biological fluids in protected forms; as such, they have potential as actionable biomarkers, supporting a theranostic approach to personalized medicine.

  • Improved techniques for nucleic acid detection promise the discovery of new ncRNA species, while developments in drug formulation and delivery support the translation of ncRNA therapeutics to clinical trials.

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Fig. 1: Non-coding RNAs and ischaemic heart disease.
Fig. 2: Non-coding RNAs as therapeutic targets in ischaemic heart disease.

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Acknowledgements

A.C. has received funding from the British Heart Foundation (Research Excellence Award 3 RE/18/5/34216 and project grant PG/22/10916). Y.D. has received funding from the EU Horizon 2020 project COVIRNA (grant agreement no. 101016072), the National Research Fund (grant no. 14/BM/8225223, C17/BM/11613033 and COVID-19/2020-1/14719577/miRCOVID), the Ministry of Higher Education and Research, and the Heart Foundation-Daniel Wagner of Luxembourg. R.K. has received funding from the Health Research Council New Zealand (grant no. 22/632). F.M. is supported by the Italian Ministry of Health projects Ricerca Corrente 2024 1.07.128, The Italian Cardiology Network IRCCS RCR-2022-23682288, RF-2019-12368521, POS T4 CAL.HUB.RIA cod. T4-AN-09, and by the Next Generation EU-NRRP M6C2 Inv. 2.1 PNRR-MAD-2022-12375790. F.M. has also received funding from Telethon Foundation (#4462 GGP19035A), by AFM-Telethon (#23054) and by Next Generation EU PNRR/2022/C9/MCID/I8 FibroThera. P.K.S. acknowledges the support of Integrated MRes/PhD 4-year studentship from a British Heart Foundation/National Heart and Lung Institute grant (FS/4yPhD/F/22/34178) and Diabetes UK grant (20/0006187). P.K.S. has also received funding from pharmaceutical companies F. Hoffmann-La Roche Ltd (Systems-PD, project ID: 5466496) and UCB Biopharma SPRL (EPINET 2). T.P. has received funding from the Swiss National Science Foundation: grants no. CRSII5_173738 and no. 31003A_182322. C.E. acknowledges the support of the following relevant awards from the British Heart Foundation: grants CH/15/1/3119, RG/20/9/35101, PG/22/11063, PG/23/11369 and RE/18/4/34215. Y.D., F.M., T.P. and C.E. were core members of the EU-CardioRNA COST Action CA17129 (www.cardiorna.eu). A.C., Y.D., F.M. and C.E. are also part of  the AtheroNET COST Action CA21153. Both are funded by COST (European Cooperation in Science and Technology; www.cost.eu). We are grateful to J. Hill for English proofing the manuscript.

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Correspondence to Costanza Emanueli.

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A.C. is a co-founder of MIRAVA Therapeutics. Y.D. holds patents and licensing agreements related to the use of RNAs for diagnostic and therapeutic purposes and is a member of the Scientific Advisory Board of the molecular diagnostics company Firalis SA. T.P. is a co-founder of Haya Therapeutics. The other authors declare no competing interests.

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Caporali, A., Anwar, M., Devaux, Y. et al. Non-coding RNAs as therapeutic targets and biomarkers in ischaemic heart disease. Nat Rev Cardiol 21, 556–573 (2024). https://doi.org/10.1038/s41569-024-01001-5

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