The role and possible mechanism of the ferroptosis-related SLC7A11/GSH/GPX4 pathway in myocardial ischemia-reperfusion injury

  • BMC Cardiovasc Disord. 2024 Oct 1;24(1):531. doi: 10.1186/s12872-024-04220-3.
Bingxin Chen  1  2 ,  Ping Fan  1 ,  Xue Song  1 ,  Mingjun Duan  3
Affiliations
  • 1. Department of Cardiac Function, The First Affiliated Hospital of Xinjiang Medical University, No. 137 Liyushan South Road, High-tech District, Urumqi, Xinjiang Uygur Autonomous Region, 830054, China.
  • 2. State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Urumqi, Xinjiang Uygur Autonomous Region, China.
  • 3. State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Animal Experimental Center of Xinjiang Medical University, No. 137 Liyushan South Road, High-tech District, Urumqi, Xinjiang Uygur Autonomous Region, 830000, China. [email protected].
PMID: 39354361 DOI: 10.1186/s12872-024-04220-3
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), Fe2+, 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.

Keywords
Ferroptosis; GPX4 enzyme; Lipid peroxidation; Membrane potential; Mitophagy; Myocardial ischemia-reperfusion injury; SLC7A11; The SLC7A11/GSH/GPX4 pathway.
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