دورية أكاديمية
Switching of hypertrophic signalling towards enhanced cardiomyocyte identity and maturity by a GATA4-targeted compound.
العنوان: | Switching of hypertrophic signalling towards enhanced cardiomyocyte identity and maturity by a GATA4-targeted compound. |
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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).) |
References: | J Biol Chem. 2002 Jul 5;277(27):24390-8. (PMID: 11994297) EMBO J. 2000 May 2;19(9):2046-55. (PMID: 10790371) Front Pharmacol. 2021 Jan 20;11:553852. (PMID: 33584253) PLoS One. 2011;6(5):e20053. (PMID: 21629792) PPAR Res. 2008;2008:253817. (PMID: 18288281) Cell. 2016 Dec 15;167(7):1734-1749.e22. (PMID: 27984724) J Mol Med (Berl). 2002 Jan;80(1):51-60. (PMID: 11862325) Mol Cell Biol. 2012 Jun;32(12):2214-23. (PMID: 22473995) Hum Mol Genet. 2013 Aug 15;22(16):3269-82. (PMID: 23595884) J Med Chem. 2019 Sep 12;62(17):8284-8310. (PMID: 31431011) Cell Rep. 2015 Nov 24;13(8):1705-16. (PMID: 26586429) Sci Rep. 2017 Aug 17;7(1):8590. (PMID: 28819274) Development. 2018 Oct 22;145(20):. (PMID: 30348673) Sci Transl Med. 2014 Jun 4;6(239):239ps6. (PMID: 24898747) Nat Rev Cardiol. 2020 Jun;17(6):341-359. (PMID: 32015528) J Thorac Cardiovasc Surg. 2017 Nov;154(5):1601-1610.e3. (PMID: 28711329) J Med Chem. 2017 Sep 28;60(18):7781-7798. (PMID: 28858485) Circ Heart Fail. 2010 May;3(3):440-50. (PMID: 20200331) Circ J. 2013;77(5):1307-14. (PMID: 23400258) Circ Res. 2020 Apr 10;126(8):1086-1106. (PMID: 32271675) Circ Res. 2012 Jun 22;111(1):5-8. (PMID: 22723217) J Mol Cell Cardiol. 2014 Jul;72:296-304. (PMID: 24735830) Genes Dis. 2020 Dec 23;8(6):891-906. (PMID: 34522716) Nature. 2003 Jul 24;424(6947):443-7. (PMID: 12845333) Stem Cells. 2015 Jul;33(7):2148-57. (PMID: 25865043) PLoS One. 2015 Dec 07;10(12):e0144145. (PMID: 26642209) Stem Cell Res Ther. 2021 Mar 18;12(1):190. (PMID: 33736688) Arch Toxicol. 2018 Sep;92(9):2897-2911. (PMID: 29987409) Nat Methods. 2014 Aug;11(8):855-60. (PMID: 24930130) Nature. 2018 Apr;556(7700):239-243. (PMID: 29618819) Proc Natl Acad Sci U S A. 2004 May 4;101(18):6975-80. (PMID: 15100413) Clin Exp Pharmacol Physiol. 2002 Apr;29(4):339-45. (PMID: 11985547) J Physiol. 2003 Apr 15;548(Pt 2):493-505. (PMID: 12640016) Sci Rep. 2018 Jun 13;8(1):9047. (PMID: 29899566) Eur J Heart Fail. 2004 Mar 15;6(3):351-4. (PMID: 14987587) Science. 2019 Apr 12;364(6436):184-188. (PMID: 30846611) EMBO Mol Med. 2017 Feb;9(2):265-279. (PMID: 28053183) Cardiovasc Res. 2001 Aug 1;51(2):217-29. (PMID: 11470461) Arch Toxicol. 2020 Jun;94(6):2113-2130. (PMID: 32185414) J Physiol. 2020 Jul;598(14):2941-2956. (PMID: 30571853) Sci Rep. 2018 Mar 15;8(1):4611. (PMID: 29545582) Semin Cell Dev Biol. 2021 Nov;119:49-60. (PMID: 33952430) J Clin Invest. 1995 Sep;96(3):1280-7. (PMID: 7657802) Cardiovasc Res. 2021 Feb 22;117(3):712-726. (PMID: 32514522) Exp Mol Med. 2022 Apr;54(4):493-502. (PMID: 35379934) J Biol Chem. 2003 Jun 27;278(26):23807-16. (PMID: 12704188) Sci Rep. 2021 Apr 8;11(1):7802. (PMID: 33833285) Cardiovasc Res. 2004 Aug 1;63(2):196-207. (PMID: 15249177) |
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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