5-Lipoxygenase Inhibition Protects Retinal Pigment Epithelium from Sodium Iodate-Induced Ferroptosis and Prevents Retinal Degeneration

• Published in: Oxidative medicine and cellular longevity Vol. 2022; pp. 1792894 - 21
• Main Authors: Lee, Jong-Jer, Chang-Chien, Guo-Ping, Lin, Sufan, Hsiao, Yu-Ting, Ke, Mu-Chan, Chen, Alexander, Lin, Tsu-Kung
• Format: Journal Article
• Language: English
• Published: United States Hindawi 2022; Hindawi Limited
• Subjects: Animals; Apoptosis; Aqueous solutions; Arachidonate 5-Lipoxygenase - genetics; Arachidonate 5-Lipoxygenase - metabolism; Cell culture; Cell Line; Diabetic retinopathy; Disease Models, Animal; Experiments; Ferroptosis; Ferroptosis - drug effects; Ferroptosis - genetics; Gene Knockdown Techniques - methods; Humans; Hydroxyurea - administration & dosage; Hydroxyurea - analogs & derivatives; Iodates - adverse effects; Laboratory animals; Lipid peroxidation; Lipids; Lipoxygenase Inhibitors - administration & dosage; Macular degeneration; Macular Degeneration - chemically induced; Macular Degeneration - metabolism; Male; Metabolism; Metabolites; Mice; Mice, Inbred C57BL; Oxidation; Oxidative stress; Oxidative Stress - drug effects; Oxidative Stress - genetics; Protective Agents - administration & dosage; Proteins; Reactive Oxygen Species - metabolism; Reagents; Retina; Retinal Pigment Epithelium - drug effects; Retinal Pigment Epithelium - metabolism; Signal Transduction - drug effects; Signal Transduction - genetics; Transfection - methods; United States > US; Taiwan
• ISSN: 1942-0900; 1942-0994
• DOI: 10.1155/2022/1792894

Excessive reactive oxygen species (ROS) contribute to damage of retinal cells and the development of retinal diseases including age-related macular degeneration (AMD). ROS result in increased metabolites of lipoxygenases (LOXs), which react with ROS to induce lipid peroxidation and may lead to ferroptosis. In this study, the effect of 5-LOX inhibition on alleviating ROS-induced cell death was evaluated using sodium iodate (NaIO3) in the retinal pigment epithelium (RPE) cell line ARPE-19 and a mouse model investigating oxidative stress in AMD. We demonstrated that NaIO3 induced cell death in the RPE cells through mechanisms including ferroptosis. Inhibition of 5-LOX with specific inhibitor, Zileuton, or siRNA knockdown of ALXO5 mitigated NaIO3-induced lipid peroxidation, mitochondrial damage, DNA impairment, and cell death in ARPE-19 cells. Additionally, in the mouse model, pretreatment with Zileuton reduced the NaIO3-induced lipid peroxidation of RPE cells, cell death in the photoreceptor layer of the retina, inflammatory responses, and degeneration of both the neuroretina and RPE monolayer cells. Our results suggest that 5-LOX plays a crucial role in ROS-induced cell death in the RPE and that regulating 5-LOX activity could be a useful approach to control ROS and ferroptosis-induced damage, which promote degeneration in retinal diseases.