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Young Hee Yoon, Jeong A Choi, Jong-uk Hwang, kyung sook cho, Jae-Young Koh; Metallothionein-3 is essential for vascular endothelial growth factor induction in a mouse model of choroidal neovascularization (CNV). Invest. Ophthalmol. Vis. Sci. 2013;54(15):327.
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© ARVO (1962-2015); The Authors (2016-present)
Metallothionein-3 (Mt3) has diverse roles in the central nervous system (CNS). By binding or releasing free zinc inside cells, it may act as cytoprotective or cytotoxic protein depending on the contexts. While the retina is a part of the CNS, the role of Mt3 in retinal disease has been sparse. We investigated the role of Mt3 in the induction of vascular endothelial growth factor (VEGF) and, subsequently, in the induction of laser-induced choroidal neovascularization (CNV).
To confirm the presence of Mt3 mRNA in the mouse eye, quantitative real-time polymerase chain reaction (qPCR) was conducted. To induce CNV in mice (2-3 months old), the Bruch’s membrane was disrupted by using argon laser. Fluorescein angiography (FA) was performed with Micron III retinal imaging system (Phoenix Research Laboratories, Inc) by an operator masked to the genetic identity of the animal. Western blots were performed for testing HIF-1α and VEGF in Mt3 wild-type (WT) and knock-out (KO) mice.
Neural retina expressed Mt3 mRNA, at the level comparable to that in the brain. Two weeks following laser treatment, Mt3 null mice exhibited much reduced CNV formation as compared with WT mice; the mean size of CNV was smaller (p<0.01), and the leakage in FA less prominent (p<0.01). While the baseline VEGF levels were similar in WT and Mt3 KO mice, VEGF expression was markedly increased 2 weeks following the laser photocoagulation, only in WT mice (113.218 pg/ml) but not in Mt3 KO mice (73.1842 pg/ml) (p<0.05). In addition, there were increases in levels of HIF-1α and VEGF in WT mice but not in KO mice. Treatment with zinc (40 µM) to cultured retinal neuronal cells significantly increased of VEGF expression, suggesting that zinc release from Mt3 was responsible for VEGF induction in laser-induced CNV.
The present results indicate that Mt3 is expressed in retinal cells, and plays a role in the development of CNV in a mouse model, possibly by modulating the VEGF pathway by releasing zinc inside cells.
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