Cardiac Actions of a Small Molecule Inhibitor Targeting GATA4–NKX2-5 Interaction

Sini Marketta Kinnunen, Marja Anneli Tölli, Mika Juhani Välimäki, Erhe Gao, Zoltan Szabo, Jaana Rysä, Monica Patricia Almeida Ferreira, Pauli J. Ohukainen, Raisa Serpi, Alexandra Correia, Ermei Makila, Jarno Salonen, Jouni Tapio Hirvonen, Helder Almeida Santos, Heikki Juhani Ruskoaho

Research output: Contribution to journalArticleScientificpeer-review

Abstract

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.
Original languageEnglish
Article number4611
JournalScientific Reports
Volume8
Number of pages14
ISSN2045-2322
DOIs
Publication statusPublished - 15 Mar 2018
MoE publication typeA1 Journal article-refereed

Fields of Science

  • TRANSCRIPTION FACTOR CSX/NKX2-5
  • CARDIOGENIC SMALL MOLECULES
  • HEART-FAILURE
  • IN-VIVO
  • ADULT HEART
  • GENE-EXPRESSION
  • MYOCARDIAL-INFARCTION
  • THERAPEUTIC TARGETS
  • PROTEIN-KINASE
  • GATA4 BINDING
  • 317 Pharmacy

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