title: Malondialdehyde induces autophagy dysfunction and VEGF secretion in the retinal pigment epithelium in age-related macular degeneration.
abstract: Age-related macular degeneration (AMD) is a major cause of blindness in developed countries and is closely related to oxidative stress, which leads to lipid peroxidation. Malondialdehyde (MDA) is a major byproduct of polyunsaturated fatty acid (PUFA) peroxidation. Increased levels of MDA have been reported in eyes of AMD patients. However, little is known about the direct relationship between MDA and AMD. Here we show the biological importance of MDA in AMD pathogenesis. We first confirmed that MDA levels were significantly increased in eyes of AMD patients. In ARPE-19 cells, a human retinal pigment epithelial cell line, MDA treatment induced vascular endothelial growth factor (VEGF) expression alternation, cell junction disruption, and autophagy dysfunction that was also observed in eyes of AMD patients. The MDA-induced VEGF increase was inhibited by autophagy-lysosomal inhibitors. Intravitreal MDA injection in mice increased laser-induced choroidal neovascularization (laser-CNV) volumes. In a mouse model fed a high-linoleic acid diet for 3 months, we found a significant increase in MDA levels, autophagic activity, and laser-CNV volumes. Our study revealed an important role of MDA, which acts not only as a marker but also as a causative factor of AMD pathogenesis-related autophagy dysfunction. Furthermore, higher dietary intake of linoleic acid promoted CNV progression in mice with increased MDA levels.
authors.affiliation: Department of Ophthalmology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Fuxiang
authors.initials: F
authors.lastname: Ye
authors.affiliation: Department of Ophthalmology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. Electronic address: h-kaneko@med.nagoya-u.ac.jp.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kaneko
authors.affiliation: Department of Radiological and Medical Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya 461-8673, Japan; Institute for Advanced Research, Nagoya University, Nagoya 464-8601, Japan.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Hayashi
authors.affiliation: Department of Ophthalmology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Takayama
authors.affiliation: Department of Ophthalmology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan; Laboratory of Bell Research Center-Department of Obstetrics and Gynecology Collaborative Research, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Shiang-Jyi
authors.initials: SJ
authors.lastname: Hwang
authors.affiliation: Department of Biomedical Sciences, Chubu University, Kasugai, Aichi 487-8501, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nishizawa
authors.affiliation: Department of Ophthalmology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Reona
authors.initials: R
authors.lastname: Kimoto
authors.affiliation: Department of Ophthalmology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Nagasaka
authors.affiliation: Department of Ophthalmology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Taichi
authors.initials: T
authors.lastname: Tsunekawa
authors.affiliation: Department of Ophthalmology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Matsuura
authors.affiliation: Department of Ophthalmology, Nagoya City University School of Medicine, Nagoya 467-8601, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Yasukawa
authors.affiliation: Department of Radiological and Medical Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya 461-8673, Japan.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Kondo
authors.affiliation: Department of Ophthalmology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Terasaki
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects; D020256:Choroidal Neovascularization / Q000378:metabolism* / Q000503:physiopathology; D005231:Fatty Acids, Unsaturated / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D008268:Macular Degeneration / Q000378:metabolism* / Q000503:physiopathology; D008315:Malondialdehyde / Q000008:administration & dosage / Q000378:metabolism*; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects; D010361:Patients; D055213:Retinal Pigment Epithelium / Q000378:metabolism / Q000473:pathology; D013552:Swine; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism
chemical_list: D005231:Fatty Acids, Unsaturated; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D008315:Malondialdehyde
keywords: Age-related macular degeneration; Autophagy; Linoleic acid; Lipid peroxidation; Malondialdehyde