1. The role and possible mechanism of the ferroptosis-related SLC7A11/GSH/GPX4 pathway in myocardial ischemia-reperfusion injury.
- Author
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Chen B, Fan P, Song X, and Duan M
- Subjects
- Animals, Male, Rats, Cell Line, Mitochondria, Heart metabolism, Mitochondria, Heart pathology, Mitochondria, Heart drug effects, Myocardial Infarction pathology, Myocardial Infarction metabolism, Myocardial Infarction genetics, Oxidative Stress, Reactive Oxygen Species metabolism, Amino Acid Transport System y+ metabolism, Amino Acid Transport System y+ genetics, Disease Models, Animal, Ferroptosis drug effects, Glutathione metabolism, Mitophagy drug effects, Myocardial Reperfusion Injury metabolism, Myocardial Reperfusion Injury pathology, Myocardial Reperfusion Injury genetics, Myocardial Reperfusion Injury prevention & control, Myocytes, Cardiac metabolism, Myocytes, Cardiac pathology, Myocytes, Cardiac drug effects, Phospholipid Hydroperoxide Glutathione Peroxidase metabolism, Phospholipid Hydroperoxide Glutathione Peroxidase genetics, Rats, Sprague-Dawley, Signal Transduction
- Abstract
Background: Myocardial ischemia-reperfusion injury (MI/RI) is an unavoidable risk event for acute myocardial infarction, with ferroptosis showing close involvement. We investigated the mechanism of MI/RI inducing myocardial injury by inhibiting the ferroptosis-related SLC7A11/glutathione (GSH)/glutathione peroxidase 4 (GPX4) pathway and activating mitophagy., Methods: A rat MI/RI model was established, with myocardial infarction area and injury assessed by TTC and H&E staining. Rat cardiomyocytes H9C2 were cultured in vitro, followed by hypoxia/reoxygenation (H/R) modeling and the ferroptosis inhibitor lipoxstatin-1 (Lip-1) treatment, or 3-Methyladenine or rapamycin treatment and overexpression plasmid (oe-SLC7A11) transfection during modeling. Cell viability and death were evaluated by CCK-8 and LDH assays. Mitochondrial morphology was observed by transmission electron microscopy. Mitochondrial membrane potential was detected by fluorescence dye JC-1. Levels of inflammatory factors, reactive oxygen species (ROS), Fe
2+ , malondialdehyde, lipid peroxidation, GPX4 enzyme activity, glutathione reductase, GSH and glutathione disulfide, and SLC7A11, GPX4, LC3II/I and p62 proteins were determined by ELISA kit, related indicator detection kits and Western blot., Results: The ferroptosis-related SLC7A11/GSH/GPX4 pathway was repressed in MI/RI rat myocardial tissues, inducing myocardial injury. H/R affected GSH synthesis and inhibited GPX4 enzyme activity by down-regulating SLC7A11, thus promoting ferroptosis in cardiomyocytes, which was averted by Lip-1. SLC7A11 overexpression improved H/R-induced cardiomyocyte ferroptosis via the GSH/GPX4 pathway. H/R activated mitophagy in cardiomyocytes. Mitophagy inhibition reversed H/R-induced cellular ferroptosis. Mitophagy activation partially averted SLC7A11 overexpression-improved H/R-induced cardiomyocyte ferroptosis. H/R suppressed the ferroptosis-related SLC7A11/GSH/GPX4 pathway by inducing mitophagy, leading to cardiomyocyte injury., Conclusions: Increased ROS under H/R conditions triggered cardiomyocyte injury by inducing mitophagy to suppress the ferroptosis-related SLC7A11/GSH/GPX4 signaling pathway activation., (© 2024. The Author(s).)- Published
- 2024
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