Protective Effects of Dexmedetomidine Against Ischemic Heart Disease and Diabetic Cardiomyopathy by Targeting Ferroptosis

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  Fig. 1.. Schematic diagram of ferroptosis. Iron accumulation: Transferrin receptor 1 (TFR1) transports extracellular ferric ions (Fe3+) into cells through endocytosis. These ions are then converted to ferrous ions (Fe2+) via the mediation of the metalloproteinase six-transmembrane epithelial antigen of prostate 3 (STEAP3) and divalent metal transporter 1 (DMT1), which are subsequently released into the cytoplasm. Heme oxygenase 1 (HO-1) releases Fe2+ from heme, further exacerbating intracellular iron accumulation. Antioxidant system: The cystine–glutamate cotransporter (X), which is composed of solute carrier family 7 member 11 (SLC7A11) and SLC3A2C–, an extracellular cysteine, enters the cytoplasm while glutamate is transported to the extracellular space. Intracellular cysteine is reduced to cysteine, which serves as a rate-limiting precursor for glutathione (GSH) synthesis. As a reducing substrate, GSH is catalyzed by glutathione peroxidase 4 (GPX4) to convert lipid peroxides (L-OOH) into nontoxic lipoyl alcohol (L-OH) while being oxidized into oxidized glutathione (GSSG). This process is crucial for scavenging excess peroxides and hydroxyl radicals. When GSH depletion or GPX4…

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  Fig. 2.. DEX regulates ferroptosis in IHD and DCM. DEX affects multiple signaling pathways, including the Nrf2, AMPK, GSK-3β, Akt-mTOR, cAMP/PKA/CREB, and Sirt3 pathways. DEX enhances SLC7A11, GPX4, and FPN but represses ACSL4. Therefore, DEX attenuates MDA, ROS, and Fe2+ levels, improves mitochondrial dysfunction, and promotes GSH and SOD generation. DEX, dexmedetomidine; IHD, ischemic heart disease; DCM, diabetic cardiomyopathy; Nrf2, nuclear factor erythroid 2-related factor 2; AMPK, AMP-activated protein kinase; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A; CREB, cAMP response element-binding protein; SLC7A11, solute carrier family 7 member 11; GPX4, glutathione peroxidase 4; FPN, ferroportin; ACSL4, long-chain acyl-CoA synthase 4; MDA, malondialdehyde; ROS, reactive oxygen species; GSH, glutathione; SOD, superoxide dismutase.