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

Forskningsoutput: TidskriftsbidragArtikelVetenskapligPeer review

Sammanfattning

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.
Originalspråkengelska
Artikelnummer4611
TidskriftScientific Reports
Volym8
Antal sidor14
ISSN2045-2322
DOI
StatusPublicerad - 15 mar 2018
MoE-publikationstypA1 Tidskriftsartikel-refererad

Vetenskapsgrenar

  • 317 Farmaci

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title = "Cardiac Actions of a Small Molecule Inhibitor Targeting GATA4–NKX2-5 Interaction",
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.",
keywords = "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",
author = "Kinnunen, {Sini Marketta} and T{\"o}lli, {Marja Anneli} and V{\"a}lim{\"a}ki, {Mika Juhani} and Erhe Gao and Zoltan Szabo and Jaana Rys{\"a} and {Almeida Ferreira}, {Monica Patricia} and {J. Ohukainen}, Pauli and Raisa Serpi and Alexandra Correia and Ermei Makila and Jarno Salonen and Hirvonen, {Jouni Tapio} and {Almeida Santos}, Helder and Ruskoaho, {Heikki Juhani}",
year = "2018",
month = "3",
day = "15",
doi = "10.1038/s41598-018-22830-8",
language = "English",
volume = "8",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",

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Cardiac Actions of a Small Molecule Inhibitor Targeting GATA4–NKX2-5 Interaction. / Kinnunen, Sini Marketta; Tölli, Marja Anneli; Välimäki, Mika Juhani; Gao, Erhe; Szabo, Zoltan; Rysä, Jaana; Almeida Ferreira, Monica Patricia; J. Ohukainen, Pauli; Serpi, Raisa; Correia, Alexandra ; Makila, Ermei; Salonen, Jarno; Hirvonen, Jouni Tapio; Almeida Santos, Helder; Ruskoaho, Heikki Juhani.

I: Scientific Reports, Vol. 8, 4611 , 15.03.2018.

Forskningsoutput: TidskriftsbidragArtikelVetenskapligPeer review

TY - JOUR

T1 - Cardiac Actions of a Small Molecule Inhibitor Targeting GATA4–NKX2-5 Interaction

AU - Kinnunen, Sini Marketta

AU - Tölli, Marja Anneli

AU - Välimäki, Mika Juhani

AU - Gao, Erhe

AU - Szabo, Zoltan

AU - Rysä, Jaana

AU - Almeida Ferreira, Monica Patricia

AU - J. Ohukainen, Pauli

AU - Serpi, Raisa

AU - Correia, Alexandra

AU - Makila, Ermei

AU - Salonen, Jarno

AU - Hirvonen, Jouni Tapio

AU - Almeida Santos, Helder

AU - Ruskoaho, Heikki Juhani

PY - 2018/3/15

Y1 - 2018/3/15

N2 - 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.

AB - 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.

KW - TRANSCRIPTION FACTOR CSX/NKX2-5

KW - CARDIOGENIC SMALL MOLECULES

KW - HEART-FAILURE

KW - IN-VIVO

KW - ADULT HEART

KW - GENE-EXPRESSION

KW - MYOCARDIAL-INFARCTION

KW - THERAPEUTIC TARGETS

KW - PROTEIN-KINASE

KW - GATA4 BINDING

KW - 317 Pharmacy

U2 - 10.1038/s41598-018-22830-8

DO - 10.1038/s41598-018-22830-8

M3 - Article

VL - 8

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

M1 - 4611

ER -