Author:
Martin Tamara P,MacDonald Eilidh A,Bradley Ashley,Watson Holly,Saxena Priyanka,Rog-Zielinska Eva A.,Fisher Simon,Elbassioni Ali Ali Mohamed,Almuzaini Ohood,Booth Catriona,Campbell Morna,Herzyk Pawel,Blyth Karen,Nixon Colin,Zentilin Lorena,Berry Colin,Braun Thomas,Giacca Mauro,McBride Martin W,Nicklin Stuart A,Cameron Ewan R,Loughrey Christopher M
Abstract
ABSTRACTMyocardial infarction is a major cause of death worldwide. Effective treatments are required that limit adverse cardiac remodelling and preserve cardiac contractility following myocardial infarction, with the aim of improving patient outcomes and preventing progression to heart failure. The perfused but hypocontractile myocardium bordering a newly created infarct is functionally distinct from the remote surviving myocardium; it is also a major determinant of adverse cardiac remodelling and whole heart contractility. Expression of the transcription factor RUNX1 is increased in the border zone at 1 day after myocardial infarction, suggesting potential for targeted therapeutic intervention. Here we demonstrate that RUNX1 drives reductions in cardiomyocyte contractility, sarcoplasmic reticulum-mediated calcium release, mitochondrial density, and the expression of genes important for oxidative phosphorylation.Antagonising RUNX1 expression via short-hairpin RNA interference preserved cardiac contractile function following myocardial infarction when delivered either via direct adenoviral delivery into the border zone or via an adeno-associated virus vector administered intravenously. Equivalent effects were obtained with a small molecule inhibitor (Ro5-3335) that reduces RUNX1 function by blocking its interaction with the essential co-factor CBFβ. Both tamoxifen-inducible Runx1-deficient and Cbfβ-deficient cardiomyocyte-specific mouse models demonstrated that antagonising RUNX1 function preserves the expression of genes important for oxidative phosphorylation following myocardial infarction. Our results confirm the translational potential of RUNX1 as a novel therapeutic target in myocardial infarction, with wider opportunities for use across a range of cardiac diseases where RUNX1 drives adverse cardiac remodelling.
Publisher
Cold Spring Harbor Laboratory
Cited by
1 articles.
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