Induction of ferroptosis by HO-1 contributes to retinal degeneration in mice with defective clearance of all-trans-retinal.

The accumulation of all-trans-retinal (atRAL) in photoreceptors and the retinal pigment epithelium (RPE), which is induced by chaos in visual (retinoid) cycle, is closely associated with the pathogenesis of dry age-related macular degeneration (AMD) and autosomal recessive Stargardt's disease (STGD1). Although we have reported that the induction of ferroptosis by atRAL is an important cause of photoreceptor loss, but its mechanisms still remain unclear. In this study, we identified heme oxygenase-1 (HO-1) as an inducer of photoreceptor ferroptosis elicited by atRAL. In atRAL-loaded photoreceptor cells, inhibition of Kelch-like ECH-associated protein 1 (KEAP1) at least in part by reactive oxygen species (ROS) production evoked the release of nuclear factor-erythroid 2-related factor-2 (NRF2) from KEAP1, followed by the translocation of active NRF2 into the nucleus where it promoted the transcription of the Ho-1 gene, thereby leading to HO-1 overexpression in the cytosol. A significant elevation of Fe2+ levels in photoreceptor cells resulted from activation of HO-1 by atRAL, and it facilitated ROS overproduction and then triggered ferroptotic cell death through ROS-mediated lipid peroxidation. Both treatment with HO-1 repressor Zinc protoporphyrin IX (ZnPP) and knockout of Ho-1 gene clearly rescued photoreceptor cells against ferroptosis arising from atRAL overload. Light-exposed Abca4-/-Rdh8-/- mice rapidly display severe defects in atRAL clearance, and serve as an acute model of dry AMD and STGD1. HO-1 activation was distinctly observed in neural retina of Abca4-/-Rdh8-/- mice after exposure to light, and it was visibly relieved by intraperitoneally injected ferroptosis inhibitor ferrostatin-1. More notably, intraperitoneal administration of ZnPP effectively alleviated both photoreceptor degeneration and RPE atrophy in Abca4-/-Rdh8-/- mice in response to light exposure by repressing HO-1-mediated ferroptosis. Our study suggests that HO-1 is a key factor that regulates atRAL-induced ferroptosis in photoreceptors and the RPE, and its inhibition may hold promises for the therapy of dry AMD and STGD1.

Idiopathic Epiretinal Membrane Surgery in Patients Aged Over 80 Years: Efficacy and Safety.

Purpose: To evaluate the efficacy and safety of idiopathic epiretinal membrane (ERM) surgery in patients aged over 80 years. Methods: Consecutive patients who underwent pars plana vitrectomy (PPV) combined with ERM and internal limiting membrane (ILM) peeling with retrobulbar anesthesia were recruited. Based on age, the patients were divided into the elderly group (≥ 80 years of age) and the control group (< 80 years of age). The best-corrected visual acuity (BCVA) and surgical complications were regarded as the main measurement indicators. Results: This study included 43 eyes from 43 patients aged 80 to 91 years and 86 eyes from 86 patients aged 54 to 79 years. Surgical intervention substantially improved BCVA both in the elderly and control groups (p = 0.005 and p < 0.001, respectively). Statistical analyses showed no significant difference in the incidence of surgical complications between the two groups (p = 0.631). The operations in either group were not delayed or canceled for the reason of complications of retrobulbar anesthesia, severe anxiety, or physical discomfort in the perioperative period. Moreover, no patient required a second operation. Also, no stroke, myocardial infarction, or death occurred during the follow-up period. All the surgical complications were treated satisfactorily. Conclusion: Our outcomes indicate that PPV combined with ERM and ILM peeling with retrobulbar anesthesia is effective and safe in elderly patients aged 80 years or older. Based on age alone, we believe that advancing age should not be the risk factor for idiopathic ERM surgery.

Effect of palmitoylethanolamide on degeneration of a human-derived retinal pigment epithelial cell induced by all-trans retinal.

AIM: To study the effect of palmitoylethanolamide (PEA) on apoptosis of retinal pigment epithelial (RPE) cells induced by all-trans retinal (atRAL) and to explore the possible molecular mechanism. METHODS: CellTiter 96® Aqueous One Solution Cell Proliferation Assay (MTS) was used to detect the effect of PEA on human-derived retinal epithelial cells (ARPE-19) viability induced by atRAL. A Leica DMi8 inverted microscope was used to observe cell morphology. Reactive oxygen species (ROS) production was evaluated with 2',7'-dichlorodihydrof-luorescein diacetate (H2DCFDA) staining and fluorescence microscopy. Expression of c-Jun N-terminal kinase (JNK), phosphorylated JNK (p-JNK), c-Jun, phosphorylated c-Jun (p-c-Jun), Bak, cleaved caspase-3, C/EBP homologous protein (CHOP), and binding (Bip) protein levels were tested by Western blot. Abca4 -/- Rdh8 -/- mice, mouse models of atRAL clearance defects which displays some symbolic characteristics of dry age-related macular degeneration (AMD) and Stargardt disease (STGD1). In the animal models, PEA was injected intraperitoneally. The full-field electroretinogram was used to detect visual function under scotopic conditions traced from mice. Optical coherence tomography showed reconstitution or thickening of the retinal pigment epithelium layer. Effect of PEA on fundus injury induced by light in Abca4-/-Rdh8-/- mice was observed by fundus photography. RESULTS: PEA ameliorated ARPE-19 cells apoptosis and inhibited ROS (including mitochondrial ROS) production induced by atRAL. PEA improved the retinal functional, prohibited both RPE and photoreceptor from death, ameliorates light-induced fundus impairment in Abca4 -/- Rdh8 -/- mice. In vitro and in vivo, PEA inhibited JNK, p-JNK, c-Jun, p-c-Jun, Bak, cleaved caspase-3, CHOP, and Bip protein levels induced by all-trans retinal in ARPE-19 cells. CONCLUSION: PEA has effect on treating RPE cells apoptosis in retinopathy caused by atRAL accumulation. PEA is a potential treatment strategy for dry AMD and STGD1. The molecular mechanism is affecting the ROS-JNK-CHOP signaling pathway partly.