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- W4387621177 abstract "Background and Aims: Duchenne muscular dystrophy (DMD) is the most common and fatal form of muscular dystrophy. DMD-associated cardiomyopathy (DMD-CM) is a major cause of morbidity and mortality in patients with DMD. Ferroptosis, a new type of regulated cell death characterized by iron-dependence and the accumulation of cell membrane lipid peroxidation, has been manifested in various cardiovascular disease conditions. However, ferroptosis has not been studied in DMD-CM. Here, we aim to determine whether ferroptosis play a potential role in DMD-CM. Methods and Results: We used a dystrophin/utrophin double knockout (mdx:utr -/- ) mouse model that displays clinical signs of DMD and DMD-CM. We performed RNA isolation from the ventricles of 3-month-old wild type (WT) and mdx:utr -/- mice (n=3) and performed RNA-Seq analysis. We found alterations of ferroptosis-related pathways such as GTP cyclohydrolase 1, transferrin receptor, glutamine transporter SLC38A1, heme oxygenase-1 (HMOX-1), and arachidonate 5-lipoxygenase (ALOX5) pathways in mdx:utr -/- hearts compared to WT hearts. Western blots confirmed the upregulation of ALOX5 and downregulation of HMOX-1, ferroptosis suppressor protein 1, and NADPH oxidase 4 in mdx:utr -/- hearts, while there was no change in glutathione peroxidase 4 (GPX4) levels. We also observed an increased level of lipid peroxidation in mdx:utr -/- hearts compared to WT as estimated by the level of malondialdehyde. Live/dead viability assays demonstrated a higher cell death rate in cardiomyocytes from mdx:utr -/- mice (53.7±7.2%, n=24) compared to those from WT mice (11.7±1.1%, n=17, p< 0.01) under control conditions. The observed cell death in mdx:utr -/- cardiomyocytes was efficiently prevented by the selective ferroptosis inhibitor ferrostatin-1 (10 μM) (7.4±1.5%, n=9, p<0.01), but not by the apoptosis inhibitor emricasan (20 μM) (56.0±1.6%, n=3, NS). Similarly, higher death rates were also observed in mdx:utr -/- than in WT cardiomyocytes when they were treated with various ferroptosis inducers such as iron overload and the GPX4 inhibitor RSL3. Conclusion: We have deciphered the link between ferroptosis and DMD-CM for the first time. Our data suggest novel targets for the treatment of DMD-CM by inhibiting ferroptosis." @default.
- W4387621177 created "2023-10-14" @default.
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- W4387621177 date "2023-08-04" @default.
- W4387621177 modified "2023-10-15" @default.
- W4387621177 title "Abstract P1156: Potential Role Of Ferroptosis In Duchenne Muscular Dystrophy-associated Cardiomyopathy" @default.
- W4387621177 doi "https://doi.org/10.1161/res.133.suppl_1.p1156" @default.
- W4387621177 hasPublicationYear "2023" @default.
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