Enhanced apoptosis in retinal pigment epithelium under inflammatory stimuli and oxidative stress

Wang, Yujuan; Shen, Defen; Wang, Vinson M.; Yu, Cheng-Rong; Wang, Renxi; Tuo, Jingsheng; Chan, Chi‐Chao

doi:10.1007/s10495-012-0750-1

Cited by 36 publications

(34 citation statements)

References 43 publications

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“…We have reported an elevated FasL-mediated RPE apoptosis under inflammation and oxidative stress in the cultured RPE cells of DKO rd8 mouse than that of WT (Wang et al, 2012). Higher levels of Bax transcript and lower ratios of Bcl2/Bax were also detected in DKO rd8 mouse eyes compared with WT (Cao et al, 2010).…”

Section: Discussionmentioning

confidence: 89%

Pigment Epithelium-Derived Factor Reduces Apoptosis and Pro-Inflammatory Cytokine Gene Expression in a Murine Model of Focal Retinal Degeneration

et al. 2013

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AMD (age-related macular degeneration) is a neurodegenerative disease causing irreversible central blindness in the elderly. Apoptosis and inflammation play important roles in AMD pathogenesis. PEDF (pigment epithelium-derived factor) is a potent neurotrophic and anti-inflammatory glycoprotein that protects the retinal neurons and photoreceptors against cell death caused by pathological insults. We studied the effects of PEDF on focal retinal lesions in DKO rd8 (Ccl2−/−/Cx3cr1−/− on C57BL/6N [Crb1rd8]) mice, a model for progressive, focal rd (retinal degeneration). First, we found a significant decrease in PEDF transcript expression in DKO rd8 mouse retina and RPE (retinal pigment epithelium) than WT (wild-type, C57BL/6N). Next, cultured DKO rd8 RPE cells secreted lower levels of PEDF protein in the media than WT. Then the right eyes of DKO rd8 mice were injected intravitreously with recombinant human PEDF protein (1 μg), followed by a subconjunctival injection of PEDF (3 μg) 4 weeks later. The untreated left eyes served as controls. The effect of PEDF was assessed by fundoscopy, ocular histopathology and A2E {[2,6-dimethyl-8-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1E,3E,5E,7E-octatetra-enyl]-1-(2-hydroxyethyl)-4-[4-methyl-6(2,6,6-trimethyl-1-cyclohexen-1-yl) 1E,3E,5E,7E-hexatrienyl]-pyridinium} levels, as well as apoptotic and inflammatory molecules. The PEDF-treated eyes showed slower progression or attenuation of the focal retinal lesions, fewer and/or smaller photoreceptor and RPE degeneration, and significantly lower A2E, relative to the untreated eyes. In addition, lower expression of apoptotic and inflammatory molecules were detected in the PEDF-treated than untreated eyes. Our results establish that PEDF potently stabilizes photoreceptor degeneration via suppression of both apoptotic and inflammatory pathways. The multiple beneficial effects of PEDF represent a novel approach for potential AMD treatment.

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Section: Discussionmentioning

confidence: 89%

Pigment Epithelium-Derived Factor Reduces Apoptosis and Pro-Inflammatory Cytokine Gene Expression in a Murine Model of Focal Retinal Degeneration

et al. 2013

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“…A number of studies found that apoptosis plays an important role in retinal cell death, both in physiological and pathological conditions, and particularly in AMD [5,31,32,33]. Dunaief et al [34], for example, demonstrated in vivo the involvement of apoptosis in RPE cell death at the margins of GA in dry AMD eyes, and Hinton et al [31] showed an involvement of apoptosis in choroidal neovascularization membranes of patients suffering from neovascular AMD.…”

Section: Discussionmentioning

confidence: 99%

“…Dunaief et al [34], for example, demonstrated in vivo the involvement of apoptosis in RPE cell death at the margins of GA in dry AMD eyes, and Hinton et al [31] showed an involvement of apoptosis in choroidal neovascularization membranes of patients suffering from neovascular AMD. Numerous in vitro investigations revealed that retinal cell apoptosis is mediated by oxidative stress [5,35,36]. In addition, apoptosis due to oxidative stress is characterized not only by elevated caspase levels, but also by an increase in the proapoptotic protein BAX and a decrease in the antiapoptotic protein Bcl-2 [27,37,38,39].…”

Section: Discussionmentioning

confidence: 99%

“…In this context, it is of importance that RPE cells are highly susceptible to oxidative stress [5]. One reason for this is that RPE cells contain numerous intracellular photoreactive compounds, including lipofuscin, melanin, and others, absorbing especially in the blue spectral range and thereby promoting the formation of oxygen radicals [6].…”

Section: Introductionmentioning

confidence: 99%

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Idebenone Prevents Oxidative Stress, Cell Death and Senescence of Retinal Pigment Epithelium Cells by Stabilizing BAX/Bcl-2 Ratio

et al. 2015

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Purpose: Age-related macular degeneration (AMD) is one of the leading causes of blindness. Degeneration of the retinal pigment epithelium (RPE) is pathognomonic for the disease, and oxidative stress plays an important role in the pathogenesis of this disease. This study investigates potential antiapoptotic and cytoprotective effects of idebenone on cultured RPE cells (ARPE-19) under conditions of oxidative stress. Methods: ARPE-19 cells were treated with 1-100 µM idebenone. Cell viability (MTT assay), induction of intracellular reactive oxygen species (ROS) and histone-associated DNA fragments in mono- and oligonucleosomes, expression of proapoptotic BAX and antiapoptotic Bcl-2 as well as senescence-associated β-galactosidase (SA-β-Gal) activity were investigated under exposure to hydrogen peroxide (H₂O₂). Results: Idebenone concentrations from 1 to 20 µM showed no toxic effects on ARPE-19 cells. When cells were treated with H₂O₂, pretreatment with 5, 7.5, 10, and 20 µM idebenone led to a significant increase in the viability of ARPE-19 cells. In addition, idebenone pretreatment significantly attenuated the induction of SA-β-Gal and intracellular ROS as well as the amount of histone-associated DNA fragments after treatment with H₂O₂. The reduction of proapoptotic BAX and the elevation of antiapoptotic Bcl-2 under idebenone show that this process is rather mediated by inhibiting H₂O₂-induced apoptosis, not necrosis. Conclusion: In this study, idebenone increased survival of ARPE-19 cells and reduced cell death, senescence, and oxidative stress by stabilizing the BAX/Bcl-2 ratio.

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“…Dysfunction of autophagic mechanisms may lead to increases in protein-misfolding and oxidative stress, contributing to the overall para-inflammatory state and driving the system towards a pathological equilibrium. We have also shown enhanced apoptosis in cultured RPE cells under inflammatory stimuli and oxidative stress (Wang et al, 2012). …”

Section: The Aging Paradigm In Amdmentioning

confidence: 93%

Aging is not a disease: Distinguishing age-related macular degeneration from aging

Ardeljan

Chan

2013

Progress in Retinal and Eye Research

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Age-related macular degeneration (AMD) is a disease of the outer retina, characterized most significantly by atrophy of photoreceptors and retinal pigment epithelium accompanied with or without choroidal neovascularization. Development of AMD has been recognized as contingent on environmental and genetic risk factors, the strongest being advanced age. In this review, we highlight pathogenic changes that destabilize ocular homeostasis and promote AMD development. With normal aging, photoreceptors are steadily lost, Bruch's membrane thickens, the choroid thins, and hard drusen may form in the periphery. In AMD, many of these changes are exacerbated in addition to the development of disease-specific factors such as soft macular drusen. Para-inflammation, which can be thought of as an intermediate between basal and robust levels of inflammation, develops within the retina in an attempt to maintain ocular homeostasis, reflected by increased expression of the anti-inflammatory cytokine IL-10 coupled with shifts in macrophage plasticity from the pro-inflammatory M1 to the anti-inflammatory M2 polarization. In AMD, imbalances in the M1 and M2 populations together with activation of retinal microglia are observed and potentially contribute to tissue degeneration. Nonetheless, the retina persists in a state of chronic inflammation and increased expression of certain cytokines and inflammasomes is observed. Since not everyone develops AMD, the vital question to ask is how the body establishes a balance between normal age-related changes and the pathological phenotypes in AMD.

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Enhanced apoptosis in retinal pigment epithelium under inflammatory stimuli and oxidative stress

Cited by 36 publications

References 43 publications

Pigment Epithelium-Derived Factor Reduces Apoptosis and Pro-Inflammatory Cytokine Gene Expression in a Murine Model of Focal Retinal Degeneration

Pigment Epithelium-Derived Factor Reduces Apoptosis and Pro-Inflammatory Cytokine Gene Expression in a Murine Model of Focal Retinal Degeneration

Idebenone Prevents Oxidative Stress, Cell Death and Senescence of Retinal Pigment Epithelium Cells by Stabilizing BAX/Bcl-2 Ratio

Aging is not a disease: Distinguishing age-related macular degeneration from aging

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