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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.
Afiliación
  • Kinnunen SM; Drug Research Program, Division of Pharmacology and Pharmacotherapy, University of Helsinki, Helsinki, Finland.
  • Tölli M; Department of Pharmacology and Toxicology, Institute of Biomedicine, University of Oulu, Oulu, Finland.
  • Välimäki MJ; Department of Pharmacology and Toxicology, Institute of Biomedicine, University of Oulu, Oulu, Finland.
  • Gao E; Drug Research Program, Division of Pharmacology and Pharmacotherapy, University of Helsinki, Helsinki, Finland.
  • Szabo Z; Department of Pharmacology and Toxicology, Institute of Biomedicine, University of Oulu, Oulu, Finland.
  • Rysä J; Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, United States of America.
  • Ferreira MPA; Department of Pharmacology and Toxicology, Institute of Biomedicine, University of Oulu, Oulu, Finland.
  • Ohukainen P; School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.
  • Serpi R; Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
  • Correia A; Computational Medicine, Faculty of Medicine, University of Oulu and Biocenter Oulu, Oulu, Finland.
  • Mäkilä E; Department of Pharmacology and Toxicology, Institute of Biomedicine, University of Oulu, Oulu, Finland.
  • Salonen J; Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
  • Hirvonen J; Laboratory of Industrial Physics, Department of Physics and Astronomy, University of Turku, Turku, Finland.
  • Santos HA; Laboratory of Industrial Physics, Department of Physics and Astronomy, University of Turku, Turku, Finland.
  • Ruskoaho H; Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
Sci Rep ; 8(1): 4611, 2018 03 15.
Article en En | MEDLINE | ID: mdl-29545582
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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Daño por Reperfusión / Factor de Transcripción GATA4 / Bibliotecas de Moléculas Pequeñas / Dominios y Motivos de Interacción de Proteínas / Proteína Homeótica Nkx-2.5 / Hipertensión / Isoxazoles / Infarto del Miocardio Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Sci Rep Año: 2018 Tipo del documento: Article País de afiliación: Finlandia Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Daño por Reperfusión / Factor de Transcripción GATA4 / Bibliotecas de Moléculas Pequeñas / Dominios y Motivos de Interacción de Proteínas / Proteína Homeótica Nkx-2.5 / Hipertensión / Isoxazoles / Infarto del Miocardio Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Sci Rep Año: 2018 Tipo del documento: Article País de afiliación: Finlandia Pais de publicación: Reino Unido