After a heart attack, a protein called RUNX1 rises sharply inside heart muscle cells, and blocking it in mice preserves the heart’s ability to pump. Heart attacks often lead to heart failure because the damaged muscle stiffens and weakens—a process called adverse remodelling. Current treatments slow this decline but do not stop it. The researchers have shown that removing RUNX1 from mouse heart cells protects contractile function after an attack, and that RUNX1 levels in patient blood correlate with how poorly the heart pumps. They have also found that a related protein, RUNX3, rises after a heart attack, though its role is unknown. This programme will identify what drives RUNX1 and RUNX3 expression, test whether blocking them works in multiple forms of heart failure, and confirm that the molecular targets found in mice also appear in human and pig heart tissue. If the targets hold up, the work will lay the groundwork for large-animal translational studies—a necessary step before any therapy could reach patients. The research is preclinical and fundamental, but it directly addresses a molecular switch that may be druggable in a condition that affects millions.
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Myocardial infarction (MI) is a leading cause of heart failure (HF) and death worldwide. Preservation of contractile function and protection against adverse cardiac remodelling are key to limiting advancement of MI to HF. We have published that expression of the Runt-related transcription factor (RUNX1) in adult cardiomyocytes is increased post-MI. Cardiomyocyte-specific Runx1-deficient mice have preserved myocardial contractility and protection against adverse cardiac remodelling. Our new data demonstrate key findings of translational importance: (1) preclinical mouse studies show that targeting RUNX1 in cardiomyocytes using adenoviral vectors preserves myocardial contractility following MI; (2) increased RUNX1 expression in the myocardium occurs in multiple HF aetiologies. RUNX1 therefore has far-reaching therapeutic potential beyond MI; (3) RUNX3 (a distinct isoform) shows increased expression in hearts post-MI with unknown therapeutic potential; and (4) RUNX1 is found in patient serum post-MI and negatively correlates with pump function. This programme will: (a) determine the drivers and impact on cardiac remodelling of increased RUNX1 and RUNX3 in mouse models of MI and HF with reduced/preserved ejection fraction; (b) establish the importance of serum RUNX1 for cardiomyocyte function; and (c) validate that key RUNX-related molecular targets found in our mouse MI model are present in human and pig myocardium, paving the way for future large animal translational studies.
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