دورية أكاديمية
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Switching of hypertrophic signalling towards enhanced cardiomyocyte identity and maturity by a GATA4-targeted compound.

التفاصيل البيبلوغرافية
العنوان: Switching of hypertrophic signalling towards enhanced cardiomyocyte identity and maturity by a GATA4-targeted compound.
المؤلفون: Pohjolainen L; Drug Research Program and Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, 00014, Helsinki, Finland., Kinnunen SM; Drug Research Program and Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, 00014, Helsinki, Finland., Auno S; Drug Research Program and Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland., Kiriazis A; Drug Research Program and Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland., Pohjavaara S; Drug Research Program and Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, 00014, Helsinki, Finland., Kari-Koskinen J; Drug Research Program and Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, 00014, Helsinki, Finland., Zore M; Drug Research Program and Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland., Jumppanen M; Drug Research Program and Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland., Yli-Kauhaluoma J; Drug Research Program and Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland., Talman V; Drug Research Program and Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, 00014, Helsinki, Finland., Ruskoaho H; Drug Research Program and Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, 00014, Helsinki, Finland., Välimäki MJ; Drug Research Program and Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, 00014, Helsinki, Finland. mika.valimaki@helsinki.fi.
المصدر: Stem cell research & therapy [Stem Cell Res Ther] 2024 Jan 02; Vol. 15 (1), pp. 5. Date of Electronic Publication: 2024 Jan 02.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: BioMed Central Country of Publication: England NLM ID: 101527581 Publication Model: Electronic Cited Medium: Internet ISSN: 1757-6512 (Electronic) Linking ISSN: 17576512 NLM ISO Abbreviation: Stem Cell Res Ther Subsets: MEDLINE
أسماء مطبوعة: Original Publication: London : BioMed Central
مواضيع طبية MeSH: Myocytes, Cardiac*/metabolism , Induced Pluripotent Stem Cells*/metabolism, Humans ; Rats ; Animals ; Hypertrophy/metabolism ; Transcription Factors/metabolism ; Signal Transduction ; GATA4 Transcription Factor/genetics ; GATA4 Transcription Factor/metabolism
مستخلص: Background: The prevalence of heart failure is constantly increasing, and the prognosis of patients remains poor. New treatment strategies to preserve cardiac function and limit cardiac hypertrophy are therefore urgently needed. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are increasingly used as an experimental platform for cardiac in vitro studies. However, in contrast to adult cardiomyocytes, hiPSC-CMs display immature morphology, contractility, gene expression and metabolism and hence express a naive phenotype that resembles more of a foetal cardiomyocyte.
Methods: A library of 14 novel compounds was synthesized in-house and screened for GATA4-NKX2-5 reporter activity and cellular toxicity. The most potent compound, 3i-1262, along with previously reported GATA4-acting compounds, were selected to investigate their effects on hypertrophy induced by endothelin-1 or mechanical stretch. Morphological changes and protein expression were characterized using immunofluorescence staining and high-content analysis. Changes in gene expression were studied using qPCR and RNA sequencing.
Results: The prototype compound 3i-1262 inhibited GATA4-NKX2-5 synergy in a luciferase reporter assay. Additionally, the isoxazole compound 3i-1262 inhibited the hypertrophy biomarker B-type natriuretic peptide (BNP) by reducing BNP promoter activity and proBNP expression in neonatal rat ventricular myocytes and hiPSC-CMs, respectively. Treatment with 3i-1262 increased metabolic activity and cardiac troponin T expression in hiPSC-CMs without affecting GATA4 protein levels. RNA sequencing analysis revealed that 3i-1262 induces gene expression related to metabolic activity and cell cycle exit, indicating a change in the identity and maturity status of hiPSC-CMs. The biological processes that were enriched in upregulated genes in response to 3i-1262 were downregulated in response to mechanical stretch, and conversely, the downregulated processes in response to 3i-1262 were upregulated in response to mechanical stretch.
Conclusions: There is currently a lack of systematic understanding of the molecular modulation and control of hiPSC-CM maturation. In this study, we demonstrated that the GATA4-interfering compound 3i-1262 reorganizes the cardiac transcription factor network and converts hypertrophic signalling towards enhanced cardiomyocyte identity and maturity. This conceptually unique approach provides a novel structural scaffold for further development as a modality to promote cardiomyocyte specification and maturity.
(© 2023. The Author(s).)
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معلومات مُعتمدة: 40395/13 Tekes; 2666621 Academy of Finland; 321564 Academy of Finland; 328909 Academy of Finland
فهرسة مساهمة: Keywords: Cardiomyocytes; GATA4; Hypertrophy; Isoxazole derivatives; Maturation
المشرفين على المادة: 0 (Transcription Factors)
0 (GATA4 protein, human)
0 (GATA4 Transcription Factor)
تواريخ الأحداث: Date Created: 20240103 Date Completed: 20240105 Latest Revision: 20240125
رمز التحديث: 20240125
مُعرف محوري في PubMed: PMC10763434
DOI: 10.1186/s13287-023-03623-x
PMID: 38167208
قاعدة البيانات: MEDLINE
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