Tae-Jun Park1,2, Jei Hyoung Park3, Ga Seul Lee4, Ji-Yoon Lee1,5, Ji Hye Shin1, Min Wook Kim1,6, Yong Sook Kim7, Jeong-Yoon Kim2, Kyoung-Jin Oh1,6, Baek-Soo Han1,6, Won-Kon Kim1,6, Youngkeun Ahn7, Jeong Hee Moon4, Jaewhan Song8, Kwang-Hee Bae1,6, Do Han Kim3, Eun-Woo Lee1 and Sang Chul Lee1,6
1Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea. 2Department of Microbiology and Molecular Biology, College of Bioscience and Biotechnology, Chungnam National University, Daejeon 34134, Korea. 3School of Life Sciences and Systems Biology Research Center, Gwangju Institute of Science and Technology (GIST), Gwangju 61005, Korea. 4Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea. 5Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea. 6Department of Functional Genomics, University of Science and Technology (UST), Daejeon 34141, Korea. 7Department of Cardiology, Chonnam National University Hospital, Gwangju, Korea. 8Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea
Correspondence: Do Han Kim or Eun-Woo Lee or Sang Chul Lee
These authors contributed equally: Tae-Jun Park, Jei Hyoung Park
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.