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...
Autores principales: | , , , , |
---|---|
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 |