Combined genetic and chemical screens indicate protective potential for EGFR inhibition to cardiomyocytes under hypoxia

Abstract The return of blood flow to ischemic heart after myocardial infarction causes ischemia–reperfusion injury. There is a clinical need for novel therapeutic targets to treat myocardial ischemia–reperfusion injury. Here we screened for targets for the treatment of ischemia–reperfusion injury us...

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Autores principales:	Juho Heliste, Anne Jokilammi, Katri Vaparanta, Ilkka Paatero, Klaus Elenius
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/b109947235e848e48d77e2e461549237
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spelling	oai:doaj.org-article:b109947235e848e48d77e2e4615492372021-12-02T16:45:47ZCombined genetic and chemical screens indicate protective potential for EGFR inhibition to cardiomyocytes under hypoxia10.1038/s41598-021-96033-z2045-2322https://doaj.org/article/b109947235e848e48d77e2e4615492372021-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-96033-zhttps://doaj.org/toc/2045-2322Abstract The return of blood flow to ischemic heart after myocardial infarction causes ischemia–reperfusion injury. There is a clinical need for novel therapeutic targets to treat myocardial ischemia–reperfusion injury. Here we screened for targets for the treatment of ischemia–reperfusion injury using a combination of shRNA and drug library analyses in HL-1 mouse cardiomyocytes subjected to hypoxia and reoxygenation. The shRNA library included lentiviral constructs targeting 4625 genes and the drug library 689 chemical compounds approved by the Food and Drug Administration (FDA). Data were analyzed using protein–protein interaction and pathway analyses. EGFR inhibition was identified as a cardioprotective mechanism in both approaches. Inhibition of EGFR kinase activity with gefitinib improved cardiomyocyte viability in vitro. In addition, gefitinib preserved cardiac contractility in zebrafish embryos exposed to hypoxia-reoxygenation in vivo. These findings indicate that the EGFR inhibitor gefitinib is a potential candidate for further studies of repurposing the drug for the treatment of myocardial infarction.Juho HelisteAnne JokilammiKatri VaparantaIlkka PaateroKlaus EleniusNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-16 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Juho Heliste Anne Jokilammi Katri Vaparanta Ilkka Paatero Klaus Elenius Combined genetic and chemical screens indicate protective potential for EGFR inhibition to cardiomyocytes under hypoxia
description	Abstract The return of blood flow to ischemic heart after myocardial infarction causes ischemia–reperfusion injury. There is a clinical need for novel therapeutic targets to treat myocardial ischemia–reperfusion injury. Here we screened for targets for the treatment of ischemia–reperfusion injury using a combination of shRNA and drug library analyses in HL-1 mouse cardiomyocytes subjected to hypoxia and reoxygenation. The shRNA library included lentiviral constructs targeting 4625 genes and the drug library 689 chemical compounds approved by the Food and Drug Administration (FDA). Data were analyzed using protein–protein interaction and pathway analyses. EGFR inhibition was identified as a cardioprotective mechanism in both approaches. Inhibition of EGFR kinase activity with gefitinib improved cardiomyocyte viability in vitro. In addition, gefitinib preserved cardiac contractility in zebrafish embryos exposed to hypoxia-reoxygenation in vivo. These findings indicate that the EGFR inhibitor gefitinib is a potential candidate for further studies of repurposing the drug for the treatment of myocardial infarction.
format	article
author	Juho Heliste Anne Jokilammi Katri Vaparanta Ilkka Paatero Klaus Elenius
author_facet	Juho Heliste Anne Jokilammi Katri Vaparanta Ilkka Paatero Klaus Elenius
author_sort	Juho Heliste
title	Combined genetic and chemical screens indicate protective potential for EGFR inhibition to cardiomyocytes under hypoxia
title_short	Combined genetic and chemical screens indicate protective potential for EGFR inhibition to cardiomyocytes under hypoxia
title_full	Combined genetic and chemical screens indicate protective potential for EGFR inhibition to cardiomyocytes under hypoxia
title_fullStr	Combined genetic and chemical screens indicate protective potential for EGFR inhibition to cardiomyocytes under hypoxia
title_full_unstemmed	Combined genetic and chemical screens indicate protective potential for EGFR inhibition to cardiomyocytes under hypoxia
title_sort	combined genetic and chemical screens indicate protective potential for egfr inhibition to cardiomyocytes under hypoxia
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/b109947235e848e48d77e2e461549237
work_keys_str_mv	AT juhoheliste combinedgeneticandchemicalscreensindicateprotectivepotentialforegfrinhibitiontocardiomyocytesunderhypoxia AT annejokilammi combinedgeneticandchemicalscreensindicateprotectivepotentialforegfrinhibitiontocardiomyocytesunderhypoxia AT katrivaparanta combinedgeneticandchemicalscreensindicateprotectivepotentialforegfrinhibitiontocardiomyocytesunderhypoxia AT ilkkapaatero combinedgeneticandchemicalscreensindicateprotectivepotentialforegfrinhibitiontocardiomyocytesunderhypoxia AT klauselenius combinedgeneticandchemicalscreensindicateprotectivepotentialforegfrinhibitiontocardiomyocytesunderhypoxia
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Combined genetic and chemical screens indicate protective potential for EGFR inhibition to cardiomyocytes under hypoxia

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