Ribonucleicacid interference or small molecule inhibition of Runx1 in the border zone prevents cardiac contractile dysfunction following myocardial infarction

Martin, T. P. et al. (2023) Ribonucleicacid interference or small molecule inhibition of Runx1 in the border zone prevents cardiac contractile dysfunction following myocardial infarction. Cardiovascular Research, 119(16), 2663–2671-2663–2671. (doi: 10.1093/cvr/cvad107) (PMID:37433039) (PMCID:PMC10730241)

Abstract

Aims: Myocardial infarction (MI) is a major cause of death worldwide. Effective treatments are required to improve recovery of cardiac function following MI, with the aim of improving patient outcomes and preventing progression to heart failure. The perfused but hypocontractile region bordering an infarct is functionally distinct from the remote surviving myocardium and is a determinant of adverse remodelling and cardiac contractility. Expression of the transcription factor RUNX1 is increased in the border zone 1-day after MI, suggesting potential for targeted therapeutic intervention. Objective: This study sought to investigate whether an increase in RUNX1 in the border zone can be therapeutically targeted to preserve contractility following MI. Methods and results: In this work we demonstrate that Runx1 drives reductions in cardiomyocyte contractility, calcium handling, mitochondrial density, and expression of genes important for oxidative phosphorylation. Both tamoxifen-inducible Runx1-deficient and essential co-factor common β subunit (Cbfβ)-deficient cardiomyocyte-specific mouse models demonstrated that antagonizing RUNX1 function preserves the expression of genes important for oxidative phosphorylation following MI. Antagonizing RUNX1 expression via short-hairpin RNA interference preserved contractile function following MI. Equivalent effects were obtained with a small molecule inhibitor (Ro5-3335) that reduces RUNX1 function by blocking its interaction with CBFβ. Conclusions: Our results confirm the translational potential of RUNX1 as a novel therapeutic target in MI, with wider opportunities for use across a range of cardiac diseases where RUNX1 drives adverse cardiac remodelling.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: MacDonald, Dr Eilidh and Martin, Dr Tamara and Raheem, Mr Anmar and Nicklin, Professor Stuart and Blyth, Professor Karen and Cameron, Professor Ewan and Herzyk, Dr Pawel and Riddell, Dr Alexandra and Berry, Professor Colin and Nixon, Mr Colin and McBride, Dr Martin and Elbassioni, Dr Ali Ali and Watson, Miss Holly and Bradley, Mrs Ashley and Loughrey, Professor Christopher and Saxena, Dr Priyanka and Almuzaini, Ohood and Fisher, Mr Simon
• Authors: Martin, T. P., MacDonald, E. A., Bradley, A., Watson, H., Saxena, P., Rog-Zielinska, E. A., Raheem, A., Fisher, S., Elbassioni, A. A. M., Almuzaini, O., Booth, C., Campbell, M., Riddell, A., Herzyk, P., Blyth, K., Nixon, C., Zentilin, L., Berry, C., Braun, T., Giacca, M., McBride, M. W., Nicklin, S. R., Cameron, E. R., and Loughrey, C.
• College/School: College of Medical Veterinary and Life Sciences > School of Biodiversity, One Health & Veterinary Medicine; College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health; College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
• Journal Name: Cardiovascular Research
• Publisher: Oxford University Press
• ISSN: 0008-6363
• ISSN (Online): 1755-3245
• Published Online: 11 July 2023
• Copyright Holders: Copyright © 2023 The Authors
• First Published: First published in Cardiovascular Research 119:2663–2671
• Publisher Policy: Reproduced under a Creative Commons License

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
173707		Institutional Strategic Support Fund (2016)	Anna Dominiczak	Wellcome Trust (WELLCOTR)	204820/Z/16/Z	Institute of Cardiovascular & Medical Sciences