Survival of Retinal Pigment Epithelium after Exposure to Prolonged Oxidative Injury: A Detailed Gene Expression and Cellular Analysis

Strunnikova, N.; Zhang, Connie; Teichberg, Diane; Cousins, Scott W.; Baffi, Judit; Becker, Kevin G.; Csaky, Karl G.

doi:10.1167/iovs.04-0311

Cited by 69 publications

(57 citation statements)

References 74 publications

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“…20 We previously found that exposure to cigarette smoke and HQ resulted in RPE membrane blebbing and sub-RPE deposits in mice. 21,22 We also demonstrated that nonlethal HQ-induced oxidative injury in cultured RPE cells results in reorganization of actin cytoskeleton and blebs formation [22][23][24][25] relevant to the accumulation of deposits. Blebbing of the plasma membrane is an early morphological sign of cell injury, which occurs immediately after exposure to a wide variety of toxic agents.…”

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confidence: 69%

“…In addition, we demonstrated that prolonged exposure of RPE cells to HQ results in actin rearrangements into aggregates and membrane blebbing, with a concomitant activation of the p38 MAPK pathway showed by immunohistochemistry. 25 However, whether HQ-induced oxidative injury can activate other MAPK signaling pathways, including extracellular signal-regulated kinase 1/2 (ERK1/2) cascade, has not been investigated. In addition, this study did not address the question of any posttranslational modifications such as dimerization and phosphorylation of Hsp27 known to regulate F-actin polymerization.…”

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confidence: 99%

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Cigarette Smoke-Related Hydroquinone Induces Filamentous Actin Reorganization and Heat Shock Protein 27 Phosphorylation through p38 and Extracellular Signal-Regulated Kinase 1/2 in Retinal Pigment Epithelium

Pons

Cousins

Csaky

et al. 2010

The American Journal of Pathology

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Retinal pigment epithelium (RPE)-derived membranous debris named blebs, may accumulate and contribute to sub-RPE deposit formation, which is the earliest sign of age-related macular degeneration (AMD). Oxidative injury to the RPE might play a significant role in AMD. However, the underlying mechanisms are unknown. We previously reported that hydroquinone (HQ), a major pro-oxidant in cigarette smoke, foodstuff, and atmospheric pollutants, induces actin rearrangement and membrane blebbing in RPE cells as well as sub-RPE deposits in mice. Here, we show for the first time that phosphorylated Heat shock protein 27 (Hsp27), a key regulator of actin filaments dynamics, is up-regulated in RPE from patients with AMD. Also, HQ-induced nonlethal oxidative injury led to Hsp27mRNA up-regulation, dimer formation , and Hsp27 phosphorylation in ARPE-19 cells. Furthermore, we found that a cross talk between p38 and extracellular signal-regulated kinase (ERK) mediates HQ-induced Hsp27 phosphorylation and actin aggregate formation, revealing ERK as a novel upstream mediator of Hsp27 phosphorylation. Finally, we demonstrated that Hsp25, p38, and ERK phosphorylation are increased in aging C57BL/6 mice chronically exposed to HQ, whereas Hsp25 expression is decreased. Our data suggest that phosphorylated Hsp27 might be a key mediator in AMD and HQ-induced oxidative injury to the RPE, which may provide helpful insights into the early cellular events associated with actin reorganization and bleb formation involved in sub-RPE deposits formation relevant to the pathogenesis of AMD.

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Cigarette Smoke-Related Hydroquinone Induces Filamentous Actin Reorganization and Heat Shock Protein 27 Phosphorylation through p38 and Extracellular Signal-Regulated Kinase 1/2 in Retinal Pigment Epithelium

Pons

Cousins

Csaky

et al. 2010

The American Journal of Pathology

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“…These cells express a fusion protein of GFP with a small G protein fragment that targets GFP to the plasma membrane (12). Therefore, membrane bleb formation can be easily visualized under an epifluorescence microscope.…”

Section: Rpe Bleb Induction and Isolation-arpe-19mentioning

confidence: 99%

Proteomics Characterization of Cell Membrane Blebs in Human Retinal Pigment Epithelium Cells

Garnica

Hawkridge

Collier

et al. 2009

Molecular & Cellular Proteomics

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Age-related macular degeneration (AMD) is the leading cause of legal blindness among the elderly population in the industrialized world, affecting about 14 million people in the United States alone. Smoking is a major environmental risk factor for AMD, and hydroquinone is a major component in cigarette smoke. Hydroquinone induces the formation of cell membrane blebs in human retinal pigment epithelium (RPE). Blebs may accumulate and eventually contribute first to sub-RPE deposits and then drusen formation, which is a prominent histopathologic feature in eyes with AMD. As an attempt to better understand the mechanisms involved in early AMD, we sought to investigate the proteomic profile of RPE blebs. Isolated blebs were subjected to SDS-PAGE fractionation, and ingel trypsin-digested peptides were analyzed by LC-MS/MS that lead to the identification of a total of 314 proteins. Identified proteins were predominantly involved in oxidative phosphorylation, cell junction, focal adhesion, cytoskeleton regulation, and immunogenic processes. Importantly basigin and matrix metalloproteinase-14, key proteins involved in extracellular matrix remodeling, were identified in RPE blebs and shown to be more prevalent in AMD patients. Altogether our findings suggest, for the first time, the potential involvement of RPE blebs in eye disease and shed light on the implication of cell-derived microvesicles in human pathology.

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“…While some individual components of cigarette smoke cause oxidative damage and apoptosis in RPE cells (31,58,63), there is no information regarding the direct effects of cigarette smoke exposure on human RPE cells. We therefore sought to investigate the molecular and cellular basis for the epidemiological association between cigarette smoke and AMD.…”

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Molecular regulation of cigarette smoke induced-oxidative stress in human retinal pigment epithelial cells: implications for age-related macular degeneration

Bertram¹,

Baglole²,

Phipps³

et al. 2009

American Journal of Physiology-Cell Physiology

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Survival of Retinal Pigment Epithelium after Exposure to Prolonged Oxidative Injury: A Detailed Gene Expression and Cellular Analysis

Abstract: RPE cells avoided cell death and recovered from prolonged oxidative injury by activating a host of defense mechanisms while simultaneously triggering genes and cellular responses that may be involved in RPE disease development.

Cited by 69 publications

References 74 publications

Cigarette Smoke-Related Hydroquinone Induces Filamentous Actin Reorganization and Heat Shock Protein 27 Phosphorylation through p38 and Extracellular Signal-Regulated Kinase 1/2 in Retinal Pigment Epithelium

Cigarette Smoke-Related Hydroquinone Induces Filamentous Actin Reorganization and Heat Shock Protein 27 Phosphorylation through p38 and Extracellular Signal-Regulated Kinase 1/2 in Retinal Pigment Epithelium

Proteomics Characterization of Cell Membrane Blebs in Human Retinal Pigment Epithelium Cells

Molecular regulation of cigarette smoke induced-oxidative stress in human retinal pigment epithelial cells: implications for age-related macular degeneration

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