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

Kinnunen, Sini; Tölli, Marja; Välimäki, Mika J.; Gao, Erhe; Szabò, Zoltán; Rysä, Jaana; Ferreira, Mónica P. A.; Ohukainen, Pauli; Serpi, Raisa; Correia, Alexandra; Mäkilä, Ermei; Salonen, Jarno; Hirvonen, Jouni; Santos, Hélder A.; Ruskoaho, Heikki

doi:10.1038/s41598-018-22830-8

Cited by 31 publications

(42 citation statements)

References 61 publications

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“…That said, an improved understanding of GATA‐dependent pathways may identify unique modifiers and specific downstream effectors for more targeted interventions. For example, small molecules targeting the interaction between GATA4 and NKX2.5 have been developed to improve left ventricular ejection fraction post myocardial infarction or pressure overload . We anticipate that this is just the beginning of many such discoveries that target GATA cofactors, PPIs, upstream regulators, and downstream targets.…”

Section: Future Perspectivesmentioning

confidence: 99%

From embryogenesis to adulthood: Critical role for GATA factors in heart development and function

2019

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Cardiac development is governed by a complex network of transcription factors (TFs) that regulate cell fates in a spatiotemporal manner. Among these, the GATA family of zinc finger TFs plays prominent roles in regulating the development of the myocardium, endocardium, and outflow tract. This family comprises six members three of which, GATA4, 5, and 6, are predominantly expressed in cardiac cells where they activate specific downstream gene targets via interactions with one another and with other TFs and signaling molecules. Their critical function in heart formation is evidenced by the phenotypes of animal models lacking these factors and by the broad spectrum of human congenital heart diseases associated with mutations in their genes. Similarly, in the postnatal heart, these proteins play significant and nonredundant roles in cardiac function, regulating adaptive stress responses including cardiomyocyte hypertrophy and survival, as well as endothelial homeostasis and angiogenesis. As such, decreased expression of either GATA4, 5, or 6 results in impaired cardiovascular homeostasis and increased risk of premature and serious cardiovascular events such as hypertension, arrhythmia, aortopathy, and heart failure. Although a great deal of progress has been made in understanding GATA‐dependent regulatory processes in the heart, the molecular mechanisms underlying the specificity of GATA factors and their upstream regulation remain incompletely understood. The knowledge and tools developed since their discovery 25 years ago should accelerate progress toward further elucidation of their mechanisms of action in health and disease. This in turn will greatly improve diagnosis and care for the millions of individuals affected by congenital and acquired cardiac disease worldwide.

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Section: Future Perspectivesmentioning

confidence: 99%

From embryogenesis to adulthood: Critical role for GATA factors in heart development and function

2019

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“…In vivo experiments showed that inhibition of GATA4-NKX2-5 transcriptional synergy has beneficial effects on cardiac function and gene expression in several experimental models of myocardial ischemia and pressure overload. 101,102 Echocardiographic evaluation showed significant improvement in left ventricular ejection fraction and fractional shortening and significant attenuation of myocardial structural changes in 3i-1000 treated mice after myocardial infarction. Accordingly, the increase of natriuretic peptide gene expression caused by myocardial infarction and the increase in ANP gene expression induced by myocardial ischemia reperfusion injury were significantly decreased by 3i-1000 in mice.…”

Section: Gata4-targeted Small Molecule Interventionsmentioning

confidence: 94%

“…In cardiomyocyte cultures, the compounds either augmented or inhibited ET-1and PE-induced increases in ANP and BNP gene expression, in line with inhibition or activation of the GATA4-NKX2-5 interaction. 100,101 Moreover, the inhibitory compound 3i-1000 significantly reduced mechanical stretch induced hypertrophic growth reflected by an increase in cardiomyocyte cell size and ANP and BNP mRNA levels in response to mechanical stretch.…”

Section: Gata4-targeted Small Molecule Interventionsmentioning

confidence: 97%

“…In vivo experiments showed that inhibition of GATA4–NKX2‐5 transcriptional synergy has beneficial effects on cardiac function and gene expression in several experimental models of myocardial ischemia and pressure overload . Echocardiographic evaluation showed significant improvement in left ventricular ejection fraction and fractional shortening and significant attenuation of myocardial structural changes in 3i‐1000 treated mice after myocardial infarction.…”

Section: Gata4‐targeted Small Molecule Interventionsmentioning

confidence: 99%

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Targeting GATA4 for cardiac repair

Välimäki

Ruskoaho

2019

IUBMB Life

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Various strategies have been applied to replace the loss of cardiomyocytes in order to restore reduced cardiac function and prevent the progression of heart disease. Intensive research efforts in the field of cellular reprogramming and cell transplantation may eventually lead to efficient in vivo applications for the treatment of cardiac injuries, representing a novel treatment strategy for regenerative medicine. Modulation of cardiac transcription factor (TF) networks by chemical entities represents another viable option for therapeutic interventions. Comprehensive screening projects have revealed a number of molecular entities acting on molecular pathways highly critical for cellular lineage commitment and differentiation, including compounds targeting Wnt‐ and transforming growth factor beta (TGFβ)‐signaling. Furthermore, previous studies have demonstrated that GATA4 and NKX2‐5 are essential TFs in gene regulation of cardiac development and hypertrophy. For example, both of these TFs are required to fully activate mechanical stretch‐responsive genes such as atrial natriuretic peptide and brain natriuretic peptide (BNP). We have previously reported that the compound 3i‐1000 efficiently inhibited the synergy of the GATA4–NKX2‐5 interaction. Cellular effects of 3i‐1000 have been further characterized in a number of confirmatory in vitro bioassays, including rat cardiac myocytes and animal models of ischemic injury and angiotensin II‐induced pressure overload, suggesting the potential for small molecule‐induced cardioprotection.

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“…Additionally, to compare different cardiomyocyte types, toxicity was studied in both hiPSC-CMs and primary neonatal rat ventricular myocytes (NRVMs). Second, as we have recently described a novel family of small-molecule compounds that affect the protein-protein interaction of transcription factors GATA4 and NKX2-5 and improve cardiac function in experimental models of myocardial infarction and hypertension (Ferreira et al 2017;Kinnunen et al 2018;Välimäki et al 2017), we aimed to investigate if the lead compound 3i-1000 has cardioprotective potential against doxorubicin cardiotoxicity in vitro and in vivo.…”

Section: Introductionmentioning

confidence: 99%

GATA4-targeted compound exhibits cardioprotective actions against doxorubicin-induced toxicity in vitro and in vivo: establishment of a chronic cardiotoxicity model using human iPSC-derived cardiomyocytes

et al. 2020

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Doxorubicin is a widely used anticancer drug that causes dose-related cardiotoxicity. The exact mechanisms of doxorubicin toxicity are still unclear, partly because most in vitro studies have evaluated the effects of short-term high-dose doxorubicin treatments. Here, we developed an in vitro model of long-term low-dose administration of doxorubicin utilizing human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Moreover, given that current strategies for prevention and management of doxorubicin-induced cardiotoxicity fail to prevent cancer patients developing heart failure, we also investigated whether the GATA4-targeted compound 3i-1000 has cardioprotective potential against doxorubicin toxicity both in vitro and in vivo. The final doxorubicin concentration used in the chronic toxicity model in vitro was chosen based on cell viability data evaluation. Exposure to doxorubicin at the concentrations of 1-3 µM markedly reduced (60%) hiPSC-CM viability already within 48 h, while a 14-day treatment with 100 nM doxorubicin concentration induced only a modest 26% reduction in hiPCS-CM viability. Doxorubicin treatment also decreased DNA content in hiPSC-CMs. Interestingly, the compound 3i-1000 attenuated doxorubicin-induced increase in pro-B-type natriuretic peptide (proBNP) expression and caspase-3/7 activation in hiPSC-CMs. Moreover, treatment with 3i-1000 for 2 weeks (30 mg/kg/day, i.p.) inhibited doxorubicin cardiotoxicity by restoring left ventricular ejection fraction and fractional shortening in chronic in vivo rat model. In conclusion, the results demonstrate that long-term exposure of hiPSC-CMs can be utilized as an in vitro model of delayed doxorubicin-induced toxicity and provide in vitro and in vivo evidence that targeting GATA4 may be an effective strategy to counteract doxorubicin-induced cardiotoxicity.

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

Cited by 31 publications

References 61 publications

From embryogenesis to adulthood: Critical role for GATA factors in heart development and function

From embryogenesis to adulthood: Critical role for GATA factors in heart development and function

Targeting GATA4 for cardiac repair

GATA4-targeted compound exhibits cardioprotective actions against doxorubicin-induced toxicity in vitro and in vivo: establishment of a chronic cardiotoxicity model using human iPSC-derived cardiomyocytes

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