Age-Related Macular Degeneration and Retinal Protein Modification by 4-Hydroxy-2-nonenal

Ethen, Cheryl M.; Reilly, Cavan; Feng, Xu; Olsen, Timothy W.; Ferrington, Deborah A.

doi:10.1167/iovs.06-1058

Cited by 83 publications

(56 citation statements)

References 69 publications

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“…Lipid peroxide formation was not altered by FeTPPS alone in treated controls. Furthermore, 4-HNE adducts, the most cytotoxic aldehyde formed during lipid-peroxidation, which can covalently modify protein residues and lead to functional impairment, were assessed using an antibody for 4-HNE (29). As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Peroxynitrite Mediates Retinal Neurodegeneration by Inhibiting Nerve Growth Factor Survival Signaling in Experimental and Human Diabetes

et al. 2008

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OBJECTIVE-Recently we have shown that diabetes-induced retinal neurodegeneration positively correlates with oxidative stress and peroxynitrite. Studies also show that peroxynitrite impairs nerve growth factor (NGF) survival signaling in sensory neurons. However, the causal role of peroxynitrite and the impact of tyrosine nitration on diabetes-induced retinal neurodegeneration and NGF survival signaling have not been elucidated. RESEARCH DESIGN AND METHODS-Expression of NGFand its receptors was examined in retinas from human and streptozotocin-induced diabetic rats and retinal ganglion cells (RGCs). Diabetic animals were treated with FeTPPS (15 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ip), which catalytically decomposes peroxynitrite to nitrate. After 4 weeks of diabetes, retinal cell death was determined by TUNEL assay. Lipid peroxidation and nitrotyrosine were determined using MDA assay, immunofluorescence, and Slot-Blot analysis. Expression of NGF and its receptors was determined by enzyme-linked immunosorbent assay (ELISA), real-time PCR, immunoprecipitation, and Western blot analyses.RESULTS-Analyses of retinal neuronal death and NGF showed ninefold and twofold increases, respectively, in diabetic retinas compared with controls. Diabetes also induced increases in lipid peroxidation, nitrotyrosine, and the pro-apoptotic p75 NTR receptor in human and rat retinas. These effects were associated with tyrosine nitration of the pro-survival TrkA receptor, resulting in diminished phosphorylation of TrkA and its downstream target, Akt. Furthermore, peroxynitrite induced neuronal death, TrkA nitration, and activation of p38 mitogen-activated protein kinase (MAPK) in RGCs, even in the presence of exogenous NGF. FeTPPS prevented tyrosine nitration, restored NGF survival signal, and prevented neuronal death in vitro and in vivo. CONCLUSIONS-Together

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Section: Resultsmentioning

confidence: 99%

Peroxynitrite Mediates Retinal Neurodegeneration by Inhibiting Nerve Growth Factor Survival Signaling in Experimental and Human Diabetes

et al. 2008

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“…22 The immunostaining pattern for these adducts was examined in mice at 3 months of age (Supplementary Figure S3) and at 18 months (Figures 5c-d). 4-HNE antibody did not label the Nxnl1 þ / þ retina but stains the inner retina and photoreceptor cell bodies of the ONL of the Nxnl1À/À mouse retina with increased intensity at 18 months.…”

Section: Resultsmentioning

confidence: 99%

The disruption of the rod-derived cone viability gene leads to photoreceptor dysfunction and susceptibility to oxidative stress

et al. 2010

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Rod-derived cone viability factor (RdCVF) is a thioredoxin-like protein, which has therapeutic potential for rod-cone dystrophies such as retinitis pigmentosa (RP). Cone loss in rodent models of RP is effectively reduced by RdCVF treatment. In this study, we investigate the physiological role of RdCVF in the retina by analyzing the phenotype of the mouse lacking the RdCVF gene, Nxnl1. Although the mice do not show an obvious developmental defect, an age-related reduction of both cone and rod function and a delay in the dark-adaptation of the retina are recorded by electroretinogram (ERG). This functional change is accompanied by a 17% reduction in cone density and a 20% reduction in thickness of the outer nuclear layer. The transcriptome of the retina reveals early changes in the expression of genes involved in programmed cell death, stress-response and redox-signaling, which is followed by a generalized injury response with increased microglial activation, GFAP, FGF2 and lipid peroxidation levels. Furthermore, cones of the mice lacking Nxnl1 are more sensitive to oxidative stress with a reduction of 65% in the cone flicker ERG amplitude measured under hyperoxic conditions. We show here that the RdCVF gene, in addition to therapeutic properties, has an essential role in photoreceptor maintenance and resistance to retinal oxidative stress.

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“…on April 1, 2019. by guest www.bloodjournal.org From peroxidation products could contribute to the pathology and progression of AMD. 52,53 Our studies indicate that HNE and its adducts may also impact appropriate vascularization of the retina, further exacerbating their pathologic impact. However, administration of the antioxidant NAC was sufficient to reduce HNE and TSP2 levels, resulting in restoration of retinal vascularization (Figures 6,7).…”

mentioning

confidence: 87%

CYP1B1 expression promotes the proangiogenic phenotype of endothelium through decreased intracellular oxidative stress and thrombospondin-2 expression

Tang¹,

Scheef²,

Wang³

et al. 2009

Blood

108

140

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Reactive species derived from cell oxygenation processes play an important role in vascular homeostasis and the pathogenesis of many diseases including retinopathy of prematurity. We show that CYP1B1-deficient (CYP1B1 ؊/؊ ) mice fail to elicit a neovascular response during oxygen-induced ischemic retinopathy. In addition, the retinal endothelial cells (ECs) prepared from CYP1B1 ؊/؊ mice are less adherent, less migratory, and fail to undergo capillary morphogenesis. These aberrant cellular responses were completely reversed when oxygen levels were lowered or an antioxidant added. CYP1B1 ؊/؊ ECs exhibited increased oxidative stress and expressed increased amounts of the antiangiogenic factor thrombospondin-2 (TSP2). Increased lipid peroxidation and TSP2 were both observed in retinas from CYP1B1 ؊/؊ mice and were reversed by administration of an antioxidant. Reexpression of CYP1B1 in CYP1B1 ؊/؊ ECs resulted in down-regulation of TSP2 expression and restoration of capillary morphogenesis. A TSP2 knockdown in CYP1B1 ؊/؊ ECs also restored capillary morphogenesis. Thus, CYP1B1 metabolizes cell products that modulate intracellular oxidative stress, which enhances production of TSP2, an inhibitor of EC migration and capillary morphogenesis. Evidence is presented that similar changes occur in retinal endothelium in vivo to limit neovascularization. (Blood. 2009;113:744-754) IntroductionPathologic angiogenesis is associated with major blinding diseases including retinopathy of prematurity, diabetic retinopathy, and age-related macular degeneration (AMD). 1 This neovascularization is driven by the hypoxic stimulus due to loss of existing vessels. The oxygen-induced ischemic retinopathy (OIR) model in mouse recapitulates this condition, whereby exposure to hyperoxia results in loss of existing retinal vessels promoting ischemia-mediated retinal neovascularization. 2 Reactive oxygen species (ROS) play an important role during angiogenesis, and their aberrant production is linked to retinopathy of prematurity and diabetic retinopathy. 3,4 In fact, antioxidants inhibit microvascular degeneration in models of diabetes and OIR. [4][5][6] The cellular mechanisms, which modulate intracellular oxidative stress, however, are not fully characterized.CYP1B1 is a member of the cytochrome P450 family of proteins. It is expressed in extrahepatic epithelial and particularly mesenchymal cells and exhibits a developmentally regulated expression pattern. This family of enzymes catalyzes a wide array of mono-oxygenase reactions targeting both foreign and endogenous lipophilic compounds including fat-soluble vitamins, steroid hormones, and polyunsaturated fatty acid (PUFA) products. 7 Many of these enzymes can function with low specificity to initiate inactivation or excretion pathways, but also function with high specificity and activity to synthesize physiologically active chemicals such as steroid hormones. 8,9 Recent studies indicate that expression of CYP enzymes in the cardiovascular system and their metabolites from arachidonic acid, pla...

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Age-Related Macular Degeneration and Retinal Protein Modification by 4-Hydroxy-2-nonenal

Cited by 83 publications

References 69 publications

Peroxynitrite Mediates Retinal Neurodegeneration by Inhibiting Nerve Growth Factor Survival Signaling in Experimental and Human Diabetes

Peroxynitrite Mediates Retinal Neurodegeneration by Inhibiting Nerve Growth Factor Survival Signaling in Experimental and Human Diabetes

The disruption of the rod-derived cone viability gene leads to photoreceptor dysfunction and susceptibility to oxidative stress

CYP1B1 expression promotes the proangiogenic phenotype of endothelium through decreased intracellular oxidative stress and thrombospondin-2 expression

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