Light-induced generation and toxicity of docosahexaenoate-derived oxidation products in retinal pigmented epithelial cells.
Cells, Cultured
Docosahexaenoic Acids
/ pharmacology
Humans
Light
/ adverse effects
Lipid Peroxidation
Lysosomes
/ metabolism
Macular Degeneration
/ metabolism
Membrane Potential, Mitochondrial
/ drug effects
Oxidation-Reduction
Oxidative Stress
/ drug effects
Retinal Pigment Epithelium
/ drug effects
A2E
Age-related macular degeneration
Carboxyethylpyrrole
Lipid oxidation
Lysosome
Mitochondrial membrane potential
Journal
Experimental eye research
ISSN: 1096-0007
Titre abrégé: Exp Eye Res
Pays: England
ID NLM: 0370707
Informations de publication
Date de publication:
04 2019
04 2019
Historique:
received:
15
04
2018
revised:
21
09
2018
accepted:
23
09
2018
pubmed:
9
10
2018
medline:
14
2
2020
entrez:
9
10
2018
Statut:
ppublish
Résumé
Oxidative cleavage of docosahexaenoate (DHA) in retinal pigmented epithelial (RPE) cells produces 4-hydroxy-7-oxohept-5-enoic acid (HOHA) esters of 2-lysophosphatidylcholine (PC). HOHA-PC spontaneously releases a membrane-permeant HOHA lactone that modifies primary amino groups of proteins and ethanolamine phospholipids to produce 2-(ω-carboxyethyl)pyrrole (CEP) derivatives. CEPs have significant pathological relevance to age-related macular degeneration (AMD) including activation of CEP-specific T-cells leading to inflammatory M1 polarization of macrophages in the retina involved in "dry AMD" and TLR2-dependent induction of angiogenesis that characterizes "wet AMD". RPE cells accumulate DHA from shed rod photoreceptor outer segments through phagocytosis and from plasma lipoproteins secreted by the liver through active uptake from the choriocapillaris. As a cell model of light-induced oxidative damage of DHA phospholipids in RPE cells, ARPE-19 cells were supplemented with DHA, with or without the lipofuscin fluorophore A2E. In this model, light exposure, in the absence of A2E, promoted the generation HOHA lactone-glutathione (GSH) adducts, depletion of intracellular GSH and a competing generation of CEPs. While DHA-rich RPE cells exhibit an inherent proclivity toward light-induced oxidative damage, photosensitization by A2E nearly doubled the amount of lipid oxidation and expanded the spectral range of photosensitivity to longer wavelengths. Exposure of ARPE-19 cells to 1 μM HOHA lactone for 24 h induced massive (50%) loss of lysosomal membrane integrity and caused loss of mitochondrial membrane potential. Using senescence-associated β-galactosidase (SA β-gal) staining that detects lysosomal β-galactosidase, we determined that exposure to HOHA lactone induces senescence in ARPE-19 cells. The present study shows that products of light-induced oxidative damage of DHA phospholipids in the absence of A2E can lead to RPE cell dysfunction. Therefore, their toxicity may be especially important in the early stages of AMD before RPE cells accumulate lipofuscin fluorophores.
Identifiants
pubmed: 30296412
pii: S0014-4835(18)30292-6
doi: 10.1016/j.exer.2018.09.012
pmc: PMC6443467
mid: NIHMS1509415
pii:
doi:
Substances chimiques
Docosahexaenoic Acids
25167-62-8
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
325-345Subventions
Organisme : NEI NIH HHS
ID : P30 EY011373
Pays : United States
Organisme : NEI NIH HHS
ID : R01 EY016813
Pays : United States
Informations de copyright
Copyright © 2018 Elsevier Ltd. All rights reserved.
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