Oxidative stress induces ferroptotic cell death in retinal pigment epithelial cells
| Autor: | Demetrios G. Vavvas, Suguru Nakagawa, Takatoshi Uchida, Megumi Honjo, Takashi Ueta, Kiyohito Totsuka, Makoto Aihara, Murilo F. Roggia |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Programmed cell death Cell Survival Necroptosis Iron Apoptosis Oxidative phosphorylation Retinal Pigment Epithelium medicine.disease_cause Article Lipid peroxidation 03 medical and health sciences Cellular and Molecular Neuroscience chemistry.chemical_compound Macular Degeneration 0302 clinical medicine medicine Ferroptosis Humans Cells Cultured Cell Death Chemistry Glutathione Sensory Systems eye diseases Cell biology Deferoxamine Ophthalmology Oxidative Stress 030104 developmental biology 030221 ophthalmology & optometry sense organs Lipid Peroxidation Reactive Oxygen Species Oxidative stress medicine.drug |
| Zdroj: | Exp Eye Res |
| ISSN: | 1096-0007 |
| Popis: | The dysfunction and cell death of retinal pigment epithelial (RPE) cells are hallmarks of late-stage dry (atrophic) age-related macular degeneration (AMD), for which no effective therapy has yet been developed. Previous studies have indicated that iron accumulation is a source of excess free radical production in RPE, and age-dependent iron accumulation in RPE is accelerated in patients with dry AMD. Although the pathogenic role of oxidative stress in RPE in the development of dry AMD is widely accepted, the mechanisms of oxidative stress-induced RPE cell death remain elusive. Here, we show that ferroptotic cell death, a mode of regulated necrosis mediated by iron and lipid peroxidation, is implicated in oxidative stress-induced RPE cell death in vitro. In ARPE-19 cells we observed that the ferroptosis inhibitors ferrostatin-1 and deferoxamine (DFO) rescued tert-butyl hydroperoxide (tBH)-induced RPE cell death more effectively than inhibitors of apoptosis or necroptosis. tBH-induced RPE cell death was accompanied by the three characteristics of ferroptotic cell death: lipid peroxidation, glutathione depletion, and ferrous iron accumulation, which were all significantly attenuated by ferrostatin-1 and DFO. Exogenous iron overload enhanced tBH-induced RPE cell death, but this effect was also attenuated by ferrostatin-1 and DFO. Furthermore, mRNA levels of numerous genes known to regulate iron metabolism were observed to be influenced by oxidative stress. Taken together, our observations suggest that multiple modes of cell death are involved in oxidative stress-induced RPE cell death, with ferroptosis playing a particularly important role. |
| Databáze: | OpenAIRE |
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