The DOI matches its Crossref record; 8 of the 8 references it cites were found in a registry or an index.
Combined Deficiency in Glutathione Peroxidase 4 and Vitamin E Causes Multiorgan Thrombus Formation and Early Death in Mice
Open accessAbstract
Rationale: Growing evidence indicates that oxidative stress contributes markedly to endothelial dysfunction. The selenoenzyme glutathione peroxidase 4 (Gpx4) is an intracellular antioxidant enzyme important for the protection of membranes by its unique activity to reduce complex hydroperoxides in membrane bilayers and lipoprotein particles. Yet a role of Gpx4 in endothelial cell function has remained enigmatic. Objective: To investigate the role of Gpx4 ablation and subsequent lipid peroxidation in the vascular compartment in vivo. Methods and Results: Endothelium-specific deletion of Gpx4 had no obvious impact on normal vascular homeostasis, nor did it impair tumor-derived angiogenesis in mice maintained on a normal diet. In stark contrast, aortic explants from endothelium-specific Gpx4 knockout mice showed a markedly reduced number of endothelial branches in sprouting assays. To shed light onto this apparent discrepancy between the in vivo and ex vivo results, we depleted mice of a second antioxidant, vitamin E, which is normally absent under ex vivo conditions. Therefore, mice were fed a vitamin E–depleted diet for 6 weeks before endothelial deletion of Gpx4 was induced by 4-hydroxytamoxifen. Surprisingly, ≈80% of the knockout mice died. Histopathological analysis revealed detachment of endothelial cells from the basement membrane and endothelial cell death in multiple organs, which triggered thrombus formation. Thromboembolic events were the likely cause of various clinical pathologies, including heart failure, renal and splenic microinfarctions, and paraplegia. Conclusions: Here, we show for the first time that in the absence of Gpx4, sufficient vitamin E supplementation is crucial for endothelial viability.
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Cites
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Role of Endothelial Dysfunction in Atherosclerosis
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“Discussion The endothelium maintains vascular homeostasis through multiple complex interactions with cells in the vessel wall and vessel lumen.(30) Considerable evidence suggests that oxidative stress is an important contributing factor in endothelial dysfunction.”
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ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition
Doll, S., Proneth, B., Tyurina, Y. Y., Panzilius, E., Kobayashi, S., Ingold, I., Irmler, M., Beckers, J., Aichler, M., Walch, A., et al. (2017) · Nature Chemical Biology · doi:10.1038/nchembio.2239 · Cited by 4,293
Self-citationInactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice
Friedmann Angeli, J. P., Schneider, M., Proneth, B., Tyurina, Y. Y., Tyurin, V. A., Hammond, V. J., Herbach, N., Aichler, M., Walch, A., Eggenhofer, E., et al. (2014) · Nature Cell Biology · doi:10.1038/ncb3064 · Cited by 3,732
Self-citationOxidized arachidonic and adrenic PEs navigate cells to ferroptosis
Kagan, V. E., Mao, G., Qu, F., Angeli, J. P. F., Doll, S., Croix, C. S., Dar, H. H., Liu, B., Tyurin, V. A., Ritov, V. B., et al. (2017) · Nature Chemical Biology · doi:10.1038/nchembio.2238 · Cited by 3,029
Self-citationLipid peroxidation and ferroptosis: The role of GSH and GPx4
Ursini, F., & Maiorino, M. (2020) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2020.02.027 · Cited by 1,954
Role of GPX4 in ferroptosis and its pharmacological implication
Seibt, T. M., Proneth, B., & Conrad, M. (2019) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2018.09.014 · Cited by 1,520
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Metadata
- Authors
- Wortmann, M., Schneider, M., Pircher, J., Hellfritsch, J., Aichler, M., Vegi, N., Kölle, P., Kuhlencordt, P., Walch, A., Pohl, U., Bornkamm, G. W., Conrad, M., & Beck, H.
- Venue
- Circulation Research
- Published
- 2013-08-02
- Volume
- 113
- Issue
- 4
- Pages
- 408-417
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- OpenAlex
- W2150802317
- Cited by
- 158
- References
- 8
- FWCI
- 7.34
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Wortmann, M., Schneider, M., Pircher, J., Hellfritsch, J., Aichler, M., Vegi, N., Kölle, P., Kuhlencordt, P., Walch, A., Pohl, U., Bornkamm, G. W., Conrad, M., & Beck, H. (2013). Combined Deficiency in Glutathione Peroxidase 4 and Vitamin E Causes Multiorgan Thrombus Formation and Early Death in Mice. Circulation Research. https://doi.org/10.1161/circresaha.113.279984
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