Cargando…

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

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 com...

Descripción completa

Detalles Bibliográficos
Autores principales: Heliste, Juho, Jokilammi, Anne, Vaparanta, Katri, Paatero, Ilkka, Elenius, Klaus
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8371130/
https://www.ncbi.nlm.nih.gov/pubmed/34404849
http://dx.doi.org/10.1038/s41598-021-96033-z
_version_ 1783739576070701056
author Heliste, Juho
Jokilammi, Anne
Vaparanta, Katri
Paatero, Ilkka
Elenius, Klaus
author_facet Heliste, Juho
Jokilammi, Anne
Vaparanta, Katri
Paatero, Ilkka
Elenius, Klaus
author_sort Heliste, Juho
collection PubMed
description 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 Online
Article
Text
id pubmed-8371130
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-83711302021-08-19 Combined genetic and chemical screens indicate protective potential for EGFR inhibition to cardiomyocytes under hypoxia Heliste, Juho Jokilammi, Anne Vaparanta, Katri Paatero, Ilkka Elenius, Klaus Sci Rep Article 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. Nature Publishing Group UK 2021-08-17 /pmc/articles/PMC8371130/ /pubmed/34404849 http://dx.doi.org/10.1038/s41598-021-96033-z Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Heliste, Juho
Jokilammi, Anne
Vaparanta, Katri
Paatero, Ilkka
Elenius, Klaus
Combined genetic and chemical screens indicate protective potential for EGFR inhibition to cardiomyocytes under hypoxia
title 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_short 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
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8371130/
https://www.ncbi.nlm.nih.gov/pubmed/34404849
http://dx.doi.org/10.1038/s41598-021-96033-z
work_keys_str_mv AT helistejuho combinedgeneticandchemicalscreensindicateprotectivepotentialforegfrinhibitiontocardiomyocytesunderhypoxia
AT jokilammianne combinedgeneticandchemicalscreensindicateprotectivepotentialforegfrinhibitiontocardiomyocytesunderhypoxia
AT vaparantakatri combinedgeneticandchemicalscreensindicateprotectivepotentialforegfrinhibitiontocardiomyocytesunderhypoxia
AT paateroilkka combinedgeneticandchemicalscreensindicateprotectivepotentialforegfrinhibitiontocardiomyocytesunderhypoxia
AT eleniusklaus combinedgeneticandchemicalscreensindicateprotectivepotentialforegfrinhibitiontocardiomyocytesunderhypoxia