PUBLICATION
Combined genetic and chemical screens indicate protective potential for EGFR inhibition to cardiomyocytes under hypoxia
- Authors
- Heliste, J., Jokilammi, A., Vaparanta, K., Paatero, I., Elenius, K.
- ID
- ZDB-PUB-210819-3
- Date
- 2021
- Source
- Scientific Reports 11: 16661 (Journal)
- Registered Authors
- Paatero, Ilkka
- Keywords
- none
- MeSH Terms
-
- Animals
- Cardiotonic Agents/pharmacology*
- Cell Hypoxia/drug effects*
- Cell Line
- Disease Models, Animal
- Drug Discovery
- ErbB Receptors/antagonists & inhibitors*
- ErbB Receptors/genetics
- Gefitinib/pharmacology*
- Hypoxia/drug therapy
- Hypoxia/genetics
- Mice
- Myocardial Reperfusion Injury/drug therapy
- Myocardial Reperfusion Injury/genetics
- Myocytes, Cardiac/drug effects*
- Myocytes, Cardiac/metabolism
- Protein Kinase Inhibitors/pharmacology*
- Zebrafish
- PubMed
- 34404849 Full text @ Sci. Rep.
Citation
Heliste, J., Jokilammi, A., Vaparanta, K., Paatero, I., Elenius, K. (2021) Combined genetic and chemical screens indicate protective potential for EGFR inhibition to cardiomyocytes under hypoxia. Scientific Reports. 11:16661.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping