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Published on: July 10, 2019
Ribonucleicacid interference or small molecule inhibition of Runx1 in the border zone prevents cardiac contractile
Tamara P Martin1, Eilidh A MacDonald1, Ashley Bradley1
1British Heart Foundation Glasgow Cardiovascular Research Centre, School of Cardiovascular and Metabolic Health, University of Glasgow, University Place, Glasgow G12 8TA, UK.
Insights
Targeting the transcription factor RUNX1 preserves cardiac contractility after myocardial infarction (MI). Reducing RUNX1 function improves recovery and offers a novel therapeutic strategy for heart attack patients.
Area of Science:
- Cardiovascular Research
- Molecular Cardiology
- Cardiac Regeneration
Background:
- Myocardial infarction (MI) is a leading cause of global mortality, necessitating treatments to enhance cardiac function recovery and prevent heart failure.
- The myocardial border zone post-MI exhibits distinct functional properties and influences adverse cardiac remodeling and contractility.
- Increased expression of the transcription factor RUNX1 in the MI border zone suggests a potential therapeutic target.
Purpose of the Study:
- To investigate the therapeutic potential of targeting RUNX1 in the myocardial border zone to preserve cardiac contractility following MI.
- To elucidate the role of RUNX1 in regulating cardiomyocyte function and gene expression after cardiac injury.
Main Methods:
- Utilized cardiomyocyte-specific Runx1-deficient and Cbfβ-deficient mouse models.
- Employed tamoxifen-inducible systems to control gene deletion.
- Applied short-hairpin RNA interference and a small molecule inhibitor (Ro5-3335) to antagonize RUNX1 function.
Main Results:
- RUNX1 deficiency or inhibition preserved the expression of genes crucial for oxidative phosphorylation in cardiomyocytes post-MI.
- Antagonizing RUNX1 function via genetic or pharmacological means improved cardiac contractility and function following MI.
- RUNX1 was shown to drive reductions in cardiomyocyte contractility, calcium handling, and mitochondrial density.
Conclusions:
- RUNX1 inhibition represents a promising therapeutic strategy for preserving cardiac function after MI.
- These findings highlight the translational potential of targeting RUNX1 in MI and other cardiac diseases characterized by adverse remodeling.
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.
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