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Murilo F. Roggia, Takashi Ueta, Imai Hirotaka, Tatsuya Inoue, Yasuhiro Tamaki, Yasuo Yanagi; Implication of GPx4 in Choroidal Neovascularization. Invest. Ophthalmol. Vis. Sci. 2012;53(14):5828.
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Oxidative stress has been implicated in the pathogenesis of age-related macular degeneration (AMD). Here we evaluate the implication of glutathione peroxidase 4 (GPx4), an antioxidant enzyme that is involved in the reduction of cell membrane-associated peroxidized phospholipid, in the choroidal neovascularization (CNV) model and basal VEGF-A expression level in the retinal pigment epithelium (RPE)/choroid.
We used three groups of mice expressing different levels of GPx4; i.e. GPx4+/– mice, GPx4+/+ mice and mice transgenically overexpressing GPx4 (GPx4+/+:Tg(GPx4)+/–). VEGF-A mRNA and protein level in the RPE/choroid was compared among the three groups before and 7 days after the CNV induction by laser treatment. Laser-induced CNV followed the standard protocol and analysis of the CNV size was performed using FITC- dextran staining of the flatmount 7 days after laser.
First we established the mechanism of VEGF-A expression before and after CNV induction. Although VEGF-A protein level was upregulated by the CNV induction, there was no difference in the VEGF-A mRNA before and after laser treatment, indicating the importance of the post-transcriptional regulation of VEGF-A in pathological CNV. Before laser treatment, GPx4 positively regulated both VEGF-A mRNA expression and protein level in the RPE/choroid. However, after laser treatment, GPx4 negatively regulated VEGF-A protein level, although VEGF-A mRNA was still positively regulated by GPx4. Consistent with the VEGF-A protein level, CNV size was two-time larger in the GPx4+/– mice than that in the mice overexpressing GPx4.
Physiologically, GPx4 increased VEGF-A expression by controlling its mRNA expression. However, in the pathological CNV, GPx4 had a protective role against CNV by a post-transcriptional modulation of VEGF-A expression.
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