University of Oulu

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

Cardiac actions of a small molecule inhibitor targeting GATA4–NKX2-5 interaction

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Author: Kinnunen, Sini M.1,2; Tölli, Marja2; Välimäki, Mika J.1,2;
Organizations: 1Drug Research Program, Division of Pharmacology and Pharmacotherapy, University of Helsinki, Helsinki, Finland
2Department of Pharmacology and Toxicology, Institute of Biomedicine, University of Oulu, Oulu, Finland
3Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, United States of America
4School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland
5Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
6Computational Medicine, Faculty of Medicine, University of Oulu and Biocenter Oulu, Oulu, Finland
7Laboratory of Industrial Physics, Department of Physics and Astronomy, University of Turku, Turku, Finland
8Helsinki Institute of Life Sciences (HiLIFE), University of Helsinki, Helsinki, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1.6 MB)
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Language: English
Published: Springer Nature, 2018
Publish Date: 2018-04-16


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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Series: Scientific reports
ISSN: 2045-2322
ISSN-E: 2045-2322
ISSN-L: 2045-2322
Volume: 8
Article number: 4611
DOI: 10.1038/s41598-018-22830-8
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
Funding: H. Ruskoaho acknowledges the Academy of Finland (grant no. 266661), the Sigrid Juselius Foundation and Finnish Foundation of Cardiovascular Research for financial support. The financial support from the Tekes large strategic research opening 3i-Regeneration (project no. 40395/13) is also gratefully acknowledged. H.A. Santos acknowledges financial support from the University of Helsinki Research Funds and the European Research Council under the European Union’s Seventh Framework Programme (FP/2007–2013, grant no. 310892). J. Rysä acknowledges financial support from the Academy of Finland (grant no 276747). M.P.A. Ferreira acknowledges financial support from Drug Research Doctoral Programme of the University of Helsinki for a Ph.D. grant.
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