Quantitative proteomic analyses reveal that GPX4 downregulation during myocardial infarction contributes to ferroptosis in cardiomyocytes

Cited 48 time in scopus
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Title
Quantitative proteomic analyses reveal that GPX4 downregulation during myocardial infarction contributes to ferroptosis in cardiomyocytes
Author(s)
Tae Jun Park; J H Park; Ga Seul Lee; Ji-Yoon Lee; Ji Hye Shin; Min Wook Kim; Y S Kim; J Y Kim; Kyoung Jin OhBaek Soo HanWon Kon Kim; Y Ahn; Jeong Hee Moon; J Song; Kwang-Hee BaeD H KimEun Woo LeeSang Chul Lee
Bibliographic Citation
Cell Death & Disease, vol. 10, no. 11, pp. 835-835
Publication Year
2019
Abstract
Ischaemic heart disease (IHD) is the leading cause of death worldwide. Although myocardial cell death plays a significant role in myocardial infarction (MI), its underlying mechanism remains to be elucidated. To understand the progression of MI and identify potential therapeutic targets, we performed tandem mass tag (TMT)-based quantitative proteomic analysis using an MI mouse model. Gene ontology (GO) analysis and gene set enrichment analysis (GSEA) revealed that the glutathione metabolic pathway and reactive oxygen species (ROS) pathway were significantly downregulated during MI. In particular, glutathione peroxidase 4 (GPX4), which protects cells from ferroptosis (an iron-dependent programme of regulated necrosis), was downregulated in the early and middle stages of MI. RNA-seq and qRT-PCR analyses suggested that GPX4 downregulation occurred at the transcriptional level. Depletion or inhibition of GPX4 using specific siRNA or the chemical inhibitor RSL3, respectively, resulted in the accumulation of lipid peroxide, leading to cell death by ferroptosis in H9c2 cardiomyoblasts. Although neonatal rat ventricular myocytes (NRVMs) were less sensitive to GPX4 inhibition than H9c2 cells, NRVMs rapidly underwent ferroptosis in response to GPX4 inhibition under cysteine deprivation. Our study suggests that downregulation of GPX4 during MI contributes to ferroptotic cell death in cardiomyocytes upon metabolic stress such as cysteine deprivation.
ISSN
2041-4889
Publisher
Springer-Nature Pub Group
DOI
http://dx.doi.org/10.1038/s41419-019-2061-8
Type
Article
Appears in Collections:
Division of Biomedical Research > Metabolic Regulation Research Center > 1. Journal Articles
Division of Research on National Challenges > Biodefense Research Center > 1. Journal Articles
Division of Biomedical Research > Disease Target Structure Research Center > 1. Journal Articles
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