A1 Refereed original research article in a scientific journal
Cardiac Actions of a Small Molecule Inhibitor Targeting GATA4-NKX2-5 Interaction
Authors: Sini M. Kinnunen, Marja Tölli, Mika J. Välimäki, Erhe Gao, Zoltan Szabo, Jaana Rysä, Mónica P. A. Ferreira, Pauli Ohukainen, Raisa Serpi, Alexandra Correia, Ermei Mäkilä,Jarno Salonen, Jouni Hirvonen, Hélder A. Santos, Heikki Ruskoaho
Publisher: NATURE PUBLISHING GROUP
Publication year: 2018
Journal: Scientific Reports
Journal name in source: SCIENTIFIC REPORTS
Journal acronym: SCI REP-UK
Article number: 4611
Volume: 8
Number of pages: 14
ISSN: 2045-2322
DOI: https://doi.org/10.1038/s41598-018-22830-8
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/30325896
Transcription factors are fundamental regulators of gene transcription, and many diseases, such as heart diseases, are associated with deregulation of transcriptional networks. In the adult heart, zinc-finger transcription factor GATA4 is a critical regulator of cardiac repair and remodelling. Previous studies also suggest that NKX2-5 plays function role as a cofactor of GATA4. We have recently reported the identification of small molecules that either inhibit or enhance the GATA4-NKX2-5 transcriptional synergy. Here, we examined the cardiac actions of a potent inhibitor (3i-1000) of GATA4-NKX2-5 interaction in experimental models of myocardial ischemic injury and pressure overload. In mice after myocardial infarction, 3i-1000 significantly improved left ventricular ejection fraction and fractional shortening, and attenuated myocardial structural changes. The compound also improved cardiac function in an experimental model of angiotensin II-mediated hypertension in rats. Furthermore, the up-regulation of cardiac gene expression induced by myocardial infarction and ischemia reduced with treatment of 3i-1000 or when micro-and nanoparticles loaded with 3i-1000 were injected intramyocardially or intravenously, respectively. The compound inhibited stretch- and phenylephrine-induced hypertrophic response in neonatal rat cardiomyocytes. These results indicate significant potential for small molecules targeting GATA4-NKX2-5 interaction to promote myocardial repair after myocardial infarction and other cardiac injuries.
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