BMP4 Mediates Oxidative Stress-induced Retinal Pigment Epithelial Cell Senescence and Is Overexpressed in Age-related Macular Degeneration

Zhu, Danhong; Wu, Jian; Spee, Christine; Ryan, Stephen J.; Hinton, David R.

doi:10.1074/jbc.m809393200

Cited by 76 publications

(75 citation statements)

References 61 publications

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“…Only a background signal was apparent in BALB/c and B6 retinas (Supplemental Figure 8). Furthermore, staining for bone morphogenic protein 4 (BMP4), a marker for oxidative stressinduced RPE senescence (27), produced a more enhanced signal in A/J RPE and inner segments of cone photoreceptors than in B6 retina at 1 month of age ( Figure 7G). …”

Section: Pathway Analysis Highlights Inflammatory Priming Coupled Witmentioning

confidence: 99%

Inflammatory priming predisposes mice to age-related retinal degeneration

Mustafi¹,

Maeda²,

Kohno³

et al. 2012

J. Clin. Invest.

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Disruption of cellular processes affected by multiple genes and accumulation of numerous insults throughout life dictate the progression of age-related disorders, but their complex etiology is poorly understood. Postmitotic neurons, such as photoreceptor cells in the retina and epithelial cells in the adjacent retinal pigmented epithelium, are especially susceptible to cellular senescence, which contributes to age-related retinal degeneration (ARD). The multigenic and complex etiology of ARD in humans is reflected by the relative paucity of effective compounds for its early prevention and treatment. To understand the genetic differences that drive ARD pathogenesis, we studied A/J mice, which develop ARD more pronounced than that in other inbred mouse models. Although our investigation of consomic strains failed to identify a chromosome associated with the observed retinal deterioration, pathway analysis of RNA-Seq data from young mice prior to retinal pathological changes revealed that increased vulnerability to ARD in A/J mice was due to initially high levels of inflammatory factors and low levels of homeostatic neuroprotective factors. The genetic signatures of an uncompensated preinflammatory state and ARD progression identified here aid in understanding the susceptible genetic loci that underlie pathogenic mechanisms of age-associated disorders, including several human blinding diseases. IntroductionAge-related disorders arise from failure of tissue maintenance and repair pathways that are accelerated by certain inherited and acquired factors (1). Long-lived nondividing cells, such as neurons, have markedly reduced tolerance to damage (2), and thus exhibit the most pronounced age-related changes. Neuronal cells in the retina are an especially attractive model system to study this phenomenon, owing to their accessibility and wellunderstood physiology. Rod and cone photoreceptors are retinal neuronal cells that initiate visual perception, a function requiring a competent neighboring retinal pigmented epithelium (RPE) for their normal operation (3). In postmitotic cells such as these photoreceptor and RPE cells, cellular senescence can ensue when shed oxidized photoreceptor outer segments (POS) are inadequately phagocytosed and digested by the RPE. This results in accumulation of damaged proteins, formation of toxic metabolic byproducts, inflammatory cell invasion, and cell death. RPE cells are the most affected because, in addition to processing POS, they serve as the conduit between photoreceptors and the choroidal blood supply for metabolite exchange (4). Acquisition of senescence-associated pathology stimulates cells to secrete various factors that contribute to tissue dysfunction. Conversely, adequate clearance of such cells can delay the onset of age-related tissue pathology (5).Aging laboratory experimental animals are important models for studying age-related pathology, especially neurodegenerative disorders, which have been shown to be affected by their genetic backgrounds (6, 7). The A/J inbred mouse ...

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Section: Pathway Analysis Highlights Inflammatory Priming Coupled Witmentioning

confidence: 99%

Inflammatory priming predisposes mice to age-related retinal degeneration

Mustafi¹,

Maeda²,

Kohno³

et al. 2012

J. Clin. Invest.

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“…p53 Is a Critical Tumor Suppressor T he critical tumor suppressor p53 plays important roles in cell-cycle arrest, apoptosis, senescence, or differentiation in response to various genotoxic and cellular stresses, including oxidative stress (73,102,133). As a guardian of the genome, the inactivation of wild-type p53 function by direct gene mutation or disruption of pathways important for p53 activation is a prerequisite for the development of most human cancers (35,92,127).…”

mentioning

confidence: 99%

p53, Oxidative Stress, and Aging

Liu

Xu²

2011

Antioxidants & Redox Signaling

272

198

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Mammalian aging is associated with elevated levels of oxidative damage of DNA, proteins, and lipids as a result of unbalanced prooxidant and antioxidant activities. Accumulating evidence indicates that oxidative stress is a major physiological inducer of aging. p53, the guardian of the genome that is important for cellular responses to oxidative stresses, might be a key coordinator of oxidative stress and aging. In response to low levels of oxidative stresses, p53 exhibits antioxidant activities to eliminate oxidative stress and ensure cell survival; in response to high levels of oxidative stresses, p53 exhibits prooxidative activities that further increase the levels of stresses, leading to cell death. p53 accomplishes these context-dependent roles by regulating the expression of a panel of genes involved in cellular responses to oxidative stresses and by modulating other pathways important for oxidative stress responses. The mechanism that switches p53 function from antioxidant to prooxidant remains unclear, but could account for the findings that increased p53 activities have been linked to both accelerated aging and increased life span in mice. Therefore, a balance of p53 antioxidant and prooxidant activities in response to oxidative stresses could be important for longevity by suppressing the accumulation of oxidative stresses and DNA damage. Antioxid. Redox Signal. 15, 1669-1678.p53 Is a Critical Tumor Suppressor

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“…In addition, cytokines released by chronic inflammation may stimulate new vessel growth. Oxidative stress can cause increased expression of bone morphogenetic protein 4 in RPE, which may increase senescence and the tendency to develop GA [104] . A variant of Tolllike receptor 3 has been reported to protect against GA, possibly by suppressing RPE apoptosis [105] .…”

Section: Pathogenesismentioning

confidence: 99%

Age-Related Macular Degeneration: Clinical Findings, Histopathology and Imaging Techniques

Zarbin

Casaroli-Marano

Rosenfeld³

2014

Developments in Ophthalmology

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Age-related macular degeneration (AMD) is the most common cause of blindness among people over age 55 years in industrialized countries. Known major risk factors for AMD include: age >55 years, history of smoking, white race, and mutations in various components of the complement system. Early AMD is characterized by the presence of drusen and pigmentary abnormalities. Late AMD is associated with central visual loss and is characterized by the presence of choroidal neovascularization and/or geographic atrophy. Early AMD is associated with a number of biochemical abnormalities including oxidative damage to retinal pigment epithelium (RPE) cells, complement deposition in the RPE-Bruch's membrane-choriocapillaris complex, lipidization of Bruch's membrane, and extracellular matrix abnormalities (e.g. collagen crosslinking, advanced glycation end product formation). Antiangiogenic drugs block the vascular leakage associated with choroidal new vessels, thus reducing retinal edema and stabilizing or restoring vision. At this time, there are no proven effective treatments for the nonexudative complications of AMD. Modern ocular imaging technologies (including spectral domain and phase variance optical coherence tomography, short- and long-wavelength fundus autofluorescence, adaptive optics-scanning laser ophthalmoscopy, and near-infrared reflectance) enable one to follow changes in the RPE, photoreceptors, and choriocapillaris quantitatively as the disease progresses. In addition, one can quantitatively assess the volume of drusen and areas of atrophy. These data, when correlated with the known histopathology of AMD, may provide useful measures of treatment efficacy that are likely to be more sensitive and reproducible than conventional end points such as visual acuity and rate of enlargement of geographic atrophy. As a result, these imaging technologies may be valuable in assessing the effects of cell-based therapy for patients with AMD.

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BMP4 Mediates Oxidative Stress-induced Retinal Pigment Epithelial Cell Senescence and Is Overexpressed in Age-related Macular Degeneration

Cited by 76 publications

References 61 publications

Inflammatory priming predisposes mice to age-related retinal degeneration

Inflammatory priming predisposes mice to age-related retinal degeneration

p53, Oxidative Stress, and Aging

Age-Related Macular Degeneration: Clinical Findings, Histopathology and Imaging Techniques

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