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

• Published in: Cell death & disease Vol. 10; no. 11; pp. 835 - 15
• Main Authors: Park, Tae-Jun, Park, Jei Hyoung, Lee, Ga Seul, Lee, Ji-Yoon, Shin, Ji Hye, Kim, Min Wook, Kim, Yong Sook, Kim, Jeong-Yoon, Oh, Kyoung-Jin, Han, Baek-Soo, Kim, Won-Kon, Ahn, Youngkeun, Moon, Jeong Hee, Song, Jaewhan, Bae, Kwang-Hee, Kim, Do Han, Lee, Eun-Woo, Lee, Sang Chul
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04-11-2019; Springer Nature B.V
• Subjects: 13/109; 13/2; 13/31; 13/89; 13/95; 38/91; 631/45/475/2290; 631/80/82/2344; 64/60; 692/699/75/230; 82/58; 82/80; Animals; Antibodies; Apoptosis; Biochemistry; Biomedical and Life Sciences; Cardiac muscle; Cardiomyocytes; Cell Biology; Cell Culture; Cell death; Cell Line; Coronary artery disease; Cysteine; Down-Regulation; Ferroptosis; Gene Expression Regulation, Enzymologic; Gene set enrichment analysis; Glutathione peroxidase; Heart attacks; Heart diseases; Humans; Immunology; Life Sciences; Metabolic pathways; Metabolism; Myocardial infarction; Myocardial Infarction - enzymology; Myocardial Infarction - pathology; Myocytes; Myocytes, Cardiac - enzymology; Myocytes, Cardiac - pathology; Neonates; Peroxide; Phospholipid Hydroperoxide Glutathione Peroxidase - biosynthesis; Proteomics; Rats; Rats, Sprague-Dawley; Reactive oxygen species; siRNA; Therapeutic applications; Transcription; Ventricle
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-019-2061-8

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.