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.
Highlights
Heart disease is the leading cause of death worldwide, and ischaemic heart disease (IHD), known as coronary artery disease (CAD), is the most common type of heart disease[1]
The results show that the interferon, IL-2-STAT5, and epithelial-mesenchymal transition (EMT) pathways were upregulated at the early stage of myocardial infarction (MI), while the reactive oxygen species (ROS) pathway, glycolysis, and fatty acid metabolism were downregulated at the middle stage (Fig. 2b)
Emerging studies have revealed that ferroptosis is implicated in several diseases, such as neurodegenerative diseases, ischaemia/reperfusion injury of the kidney, and cancer[33,57]
Summary
Heart disease is the leading cause of death worldwide, and ischaemic heart disease (IHD), known as coronary artery disease (CAD), is the most common type of heart disease[1]. Cardiac ischaemia can induce the death of cardiomyocytes, and the damaged heart tissues are immediately replaced with fibrotic scar tissue[2]. Official journal of the Cell Death Differentiation Association. Oxidative stress is known to mediate cardiac tissue damage by inducing cardiomyocyte death[15,16]. Reduced expression or activity of several antioxidant enzymes, including superoxide dismutase (SOD), glutathione peroxidase 1 (GPx1) and catalase (CAT), during MI has been reported to be associated with an increase in reactive oxygen species (ROS)[17]. Upon MI, the levels of glutathione (GSH), a key cellular antioxidant, were decreased in cardiomyocytes and heart tissues due to deregulated glucose metabolism and growth factor signalling, contributing to cardiomyocyte death[18,19]. Several antioxidants relieved the symptoms of MI in clinical studies, suggesting that excessive ROS contributes to the progression of MI16
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