Cardiac actions of a small molecule inhibitor targeting GATA4–NKX2-5 interaction
Kinnunen, Sini M.; Tölli, Marja; Välimäki, Mika J.; Gao, Erhe; Szabo, Zoltan; Rysä, Jaana; Ferreira, Mónica P. A.; Ohukainen, Pauli; Serpi, Raisa; Correia, Alexandra; Mäkilä, Ermei; Salonen, Jarno; Hirvonen, Jouni; Santos, Hélder A.; Ruskoaho, Heikki (2018-03-15)
Kinnunen, S., Tölli, M., Välimäki, M., Gao, E., Szabo, Z., Rysä, J., Ferreira, M., Ohukainen, P., Serpi, R., Correia, A., Mäkilä, E., Salonen, J., Hirvonen, J., Santos, H., Ruskoaho, H. (2018) Cardiac Actions of a Small Molecule Inhibitor Targeting GATA4–NKX2-5 Interaction. Scientific Reports, 8, 4611. doi:10.1038/s41598-018-22830-8
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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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