Extracellular superoxide dismutase (SOD3) regulates oxidative stress at the vitreoretinal interface

Katherine J Wert; Gabriel Velez; Madeline R Cross; Brett A Wagner; Melissa L Teoh-Fitzgerald; Garry R Buettner; J. Jason McAnany; Alicia Olivier; Stephen H Tsang; Matthew M Harper; Frederick E Domann; Alexander G Bassuk; Vinit B Mahajan

doi:10.1016/j.freeradbiomed.2018.06.024

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Extracellular superoxide dismutase (SOD3) regulates oxidative stress at the vitreoretinal interface

Journal article

Open access

Peer reviewed

Extracellular superoxide dismutase (SOD3) regulates oxidative stress at the vitreoretinal interface

Katherine J Wert, Gabriel Velez, Madeline R Cross, Brett A Wagner, Melissa L Teoh-Fitzgerald, Garry R Buettner, J. Jason McAnany, Alicia Olivier, Stephen H Tsang, Matthew M Harper, …

Free radical biology & medicine, Vol.124, pp.408-419

08/20/2018

DOI: 10.1016/j.freeradbiomed.2018.06.024

PMCID: PMC6233711

PMID: 29940351

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Abstract

Oxidative stress is a pathogenic feature in vitreoretinal disease. However, the ability of the inner retina to manage metabolic waste and oxidative stress is unknown. Proteomic analysis of antioxidants in the human vitreous, the extracellular matrix opposing the inner retina, identified superoxide dismutase-3 (SOD3) that localized to a unique matrix structure in the vitreous base and cortex. To determine the role of SOD3, Sod3-/- mice underwent histological and clinical phenotyping. Although the eyes were structurally normal, at the vitreoretinal interface Sod3-/- mice demonstrated higher levels of 3-nitrotyrosine, a key marker of oxidative stress. Pattern electroretinography also showed physiological signaling abnormalities within the inner retina. Vitreous biopsies and epiretinal membranes collected from patients with diabetic vitreoretinopathy (DVR) and a mouse model of DVR showed significantly higher levels of nitrates and/or 3-nitrotyrosine oxidative stress biomarkers suggestive of SOD3 dysfunction. This study analyzes the molecular pathways that regulate oxidative stress in human vitreous substructures. The absence or dysregulation of the SOD3 antioxidant at the vitreous base and cortex results in increased oxidative stress and tissue damage to the inner retina, which may underlie DVR pathogenesis and other vitreoretinal diseases. [Display omitted] •First study to analyze SOD3 in individual human vitreous substructures.•SOD3 is localized specifically to the vitreous base and cortex.•The loss of Sod3 causes increased oxidative stress at the vitreoretinal interface.•The loss of Sod3 in the mouse causes inner retina dysfunction.•SOD3 is a possible therapeutic target for various human vitreoretinal diseases.

Vitreous substructures

Diabetic retinopathy

Knockout mouse

Metabolic dysregulation

Proteomics

Vitreous base

Extracellular matrix

Vitreous cortex

Antioxidant

Details

Title: Subtitle: Extracellular superoxide dismutase (SOD3) regulates oxidative stress at the vitreoretinal interface
Creators: Katherine J Wert - Byers Eye Institute, Department of Ophthalmology, Stanford University, Palo Alto, CA, United States
Gabriel Velez - Byers Eye Institute, Department of Ophthalmology, Stanford University, Palo Alto, CA, United States
Madeline R Cross - Department of Pediatrics, University of Iowa, Iowa City, IA, United States
Brett A Wagner - Department of Radiation Oncology, Carver College of Medicine, University of Iowa, Iowa City, IA, United States
Melissa L Teoh-Fitzgerald - Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States
Garry R Buettner - Department of Radiation Oncology, Carver College of Medicine, University of Iowa, Iowa City, IA, United States
J. Jason McAnany - Department of Ophthalmology, University of Illinois at Chicago, Chicago, IL, United States
Alicia Olivier - Division of Comparative Pathology, Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA, United States
Stephen H Tsang - Bernard and Shirlee Brown Glaucoma Laboratory and Barbara & Donald Jonas Laboratory of Regenerative Medicine, Columbia University, New York, NY, United States
Matthew M Harper - Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, IA, United States
Frederick E Domann - Department of Radiation Oncology, Carver College of Medicine, University of Iowa, Iowa City, IA, United States
Alexander G Bassuk - Department of Pediatrics, University of Iowa, Iowa City, IA, United States
Vinit B Mahajan - Byers Eye Institute, Department of Ophthalmology, Stanford University, Palo Alto, CA, United States
Resource Type: Journal article
Publication Details: Free radical biology & medicine, Vol.124, pp.408-419
DOI: 10.1016/j.freeradbiomed.2018.06.024
PMID: 29940351
PMCID: PMC6233711
NLM abbreviation: Free Radic Biol Med
ISSN: 0891-5849
eISSN: 1873-4596
Publisher: Elsevier Inc
Grant note: DOI: 10.13039/100000002, name: NIH, award: R01EY026682, R01EY024665, R01EY025225, R01EY024698, R21AG050437 and P30EY026877, F30EYE027986 and T32GM007337; DOI: 10.13039/100000862, name: Doris Duke Charitable Foundation, award: 2013103; name: National Cancer Institute Core, award: 5P30EY019007, R01EY018213, R01EY024698, R21AG050437, 5P30CA013696; name: Tistou and Charlotte Kerstan Foundation; name: Schneeweiss Stem Cell Fund, award: C029572; name: Joel Hoffman Fund; name: Professor Gertrude Rothschild Stem Cell Foundation; name: Gebroe Family Foundation
Language: English
Date published: 08/20/2018
Academic Unit: Neurology; Stead Family Department of Pediatrics; Pathology; Iowa Neuroscience Institute; Surgery; Biology; Radiation Oncology; Neurology (Pediatrics); Ophthalmology and Visual Sciences
Record Identifier: 9984047667102771

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