Abstract | PURPOSE: The incidence of blindness is increasing, in part, because of abnormal ocular neovascularization. Anti- VEGF therapies have yielded impressive results; however, they are not a cure for blindness. Recently, metallothioneins (MTs) 1 and 2 have been implicated in the process of angiogenesis. Therefore, we investigated whether MT-1 and MT-2 were also involved in ocular neovascularization. METHODS: The concentrations of MT-1 and MT-2 (hereafter MT-1/2) were observed by ELISA. We examined the role of MT-1/2 in ocular neovascularization by using both an oxygen-induced retinopathy (OIR) model and a laser-induced choroidal neovascularization (CNV) model. We investigated the localization of MT-1/2 in retina. Furthermore, we investigated the expression of hypoxia-inducible factor (HIF)-1α and VEGF in OIR. In vitro, we investigated the degradation of HIF-1α. RESULTS: The MT-1/2 were significantly elevated in proliferative diabetic retinopathy patients. Ocular neovascularization, which was induced in both the OIR model and the CNV model, was decreased in MT-1/2 knockout (KO) mice. We confirmed that although MT-1/2 was expressed throughout the murine retina, its expression levels were highest in the endothelial cells. Further, OIR enhanced MT-1/2 expression in the retina. Interestingly, in the OIR model, both HIF-1α and VEGF levels were significantly decreased in the retina of MT-1/2 KO mice. In addition, we found that knockdown of MT-1/2 accelerated ubiquitination of HIF-1α. CONCLUSIONS: These results indicate that MT-1/2 are involved in retinal and choroidal neovascularization, and that MT-1/2 might be a new therapeutic target in diseases in which ocular angiogenesis is implicated.
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Authors | Shinsuke Nakamura, Masamitsu Shimazawa, Yuki Inoue, Shinsuke Takata, Yasushi Ito, Kazuhiro Tsuruma, Tsunehiko Ikeda, Akiko Honda, Masahiko Satoh, Hideaki Hara |
Journal | Investigative ophthalmology & visual science
(Invest Ophthalmol Vis Sci)
Vol. 55
Issue 10
Pg. 6851-6860
(Sep 23 2014)
ISSN: 1552-5783 [Electronic] United States |
PMID | 25249600
(Publication Type: Journal Article)
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Copyright | Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc. |
Chemical References |
- Matrix Metalloproteinase 2
- Matrix Metalloproteinase 1
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Topics |
- Aged
- Animals
- Blotting, Western
- Disease Models, Animal
- Enzyme-Linked Immunosorbent Assay
- Eye Diseases
(enzymology, pathology)
- Female
- Fluorescein Angiography
- Fundus Oculi
- Humans
- Immunoblotting
- Immunohistochemistry
- Male
- Matrix Metalloproteinase 1
(metabolism)
- Matrix Metalloproteinase 2
(metabolism)
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Middle Aged
- Neovascularization, Pathologic
(enzymology, pathology)
- Vitreous Body
(enzymology)
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