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Oxalomalate reduces expression and secretion of vascular endothelial growth factor in the retinal pigment epithelium and inhibits angiogenesis: Implications for age-related macular degeneration

Authors
Kim, Sung HwanKim, HyunjinKu, Hyeong JunPark, Jung HyunCha, HanvitLee, SeoyoonLee, Jin HyupPark, Jeen-Woo
Issue Date
12월-2016
Publisher
ELSEVIER SCIENCE BV
Keywords
VEGF; Retinal pigment epithelium; Oxalomalate; Reactive oxygen species
Citation
REDOX BIOLOGY, v.10, pp.211 - 220
Indexed
SCIE
SCOPUS
Journal Title
REDOX BIOLOGY
Volume
10
Start Page
211
End Page
220
URI
https://scholar.korea.ac.kr/handle/2021.sw.korea/86762
DOI
10.1016/j.redox.2016.10.008
ISSN
2213-2317
Abstract
Clinical and experimental observations indicate a critical role for vascular endothelial growth factor (VEGF), secreted by the retinal pigment epithelium (RPE), in pathological angiogenesis and the development of choroidal neovascularization (CNV) in age-related macular degeneration (AMD). RPE-mediated VEGF expression, leading to angiogenesis, is a major signaling mechanism underlying ocular neovascular disease. Inhibiting this signaling pathway with a therapeutic molecule is a promising anti-angiogenic strategy to treat this disease with potentially fewer side effects. Oxalomalate (OMA) is a competitive inhibitor of NADP(+)-dependent isocitrate dehydrogenase (IDH), which plays an important role in cellular signaling pathways regulated by reactive oxygen species (ROS). Here, we have investigated the inhibitory effect of OMA on the expression of VEGF, and the associated underlying mechanism of action, using in vitro and in vivo RPE cell models of AMD. We found that OMA reduced the expression and secretion of VEGF in RPE cells, and consequently inhibited CNV formation. This function of OMA was linked to its capacity to activate the pVHL-mediated HIF-1 alpha degradation in these cells, partly via a ROS-dependent ATM signaling axis, through inhibition of IDH enzymes. These findings reveal a novel role for OMA in inhibiting RPE-derived VEGF expression and angiogenesis, and suggest unique therapeutic strategies for treating pathological angiogenesis and AMD development.
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