Empagliflozin Attenuates Ferroptosis in Acute Myocardial Infarction via the AMPK/NRF2/SLC7A11 Signaling Pathway
Abstract
Emerging evidence implicates ferroptosis in myocardial ischemic injury. This study aimed to investigate whether empagliflozin (EMP) suppresses ferroptosis in acute myocardial infarction (AMI) via the AMP-activated protein kinase (AMPK)/nuclear factor erythroid 2-related factor 2 (NRF2)/solute carrier family 7 member 11 (SLC7A11) pathway.Hypoxia/reoxygenation (H/R)-injured HL-1 cardiomyocytes were treated with EMP (10, 20, 30 μM). Cell viability, morphology, damage, and apoptosis were assessed by CCK-8, inverted microscopy, lactate dehydrogenase (LDH) release, and flow cytometry. H/R-injured cells were treated with 30 μM EMP and/or ferrostatin-1 (Fer-1), followed by measurements of Fe2+, malondialdehyde (MDA), glutathione (GSH), reactive oxygen species (ROS), superoxide dismutase (SOD), lipid ROS (C11-BODIPY), ferroptosis-related proteins [SLC7A11, glutathione peroxidase 4 (GPX4), phospho-AMPK (p-AMPK), AMPK, NRF2 using Western blot], and NRF2 nuclear translocation (using immunofluorescence). An AMI mouse model was established. Myocardial pathology and infarct size were evaluated, and AMPK/NRF2/SLC7A11 pathway proteins and myocardial Fe2+/MDA/GSH levels were measured.EMP partially reversed H/R-induced cardiomyocyte shrinkage and membrane rupture, reduced viability, elevated LDH, and increased apoptosis. Among cell death inhibitors, Fer-1 exerted maximal protection, indicating ferroptosis may be the predominant death type in H/R-injured HL-1 cardiomyocytes. EMP mirrored the…
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