Oxalomalate reduces expression and secretion of vascular endothelial growth factor in the retinal pigment epithelium and inhibits angiogenesis: Implications for age-related macular degeneration.
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-1α 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.
School of Life Sciences and Biotechnology, BK21 Plus KNU Creative BioResearch Group, College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea.
Sung Hwan
SH
Kim
School of Life Sciences and Biotechnology, BK21 Plus KNU Creative BioResearch Group, College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea.
Hyunjin
H
Kim
School of Life Sciences and Biotechnology, BK21 Plus KNU Creative BioResearch Group, College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea.
Hyeong Jun
HJ
Ku
Department of Food and Biotechnology, Korea University, Sejong, Republic of Korea.
Jung Hyun
JH
Park
School of Life Sciences and Biotechnology, BK21 Plus KNU Creative BioResearch Group, College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea.
Hanvit
H
Cha
School of Life Sciences and Biotechnology, BK21 Plus KNU Creative BioResearch Group, College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea.
Seoyoon
S
Lee
Department of Food and Biotechnology, Korea University, Sejong, Republic of Korea; Institutes of Natural Sciences, Korea University, Sejong, Republic of Korea. Electronic address: jinhyuplee@korea.ac.kr.
Jin Hyup
JH
Lee
School of Life Sciences and Biotechnology, BK21 Plus KNU Creative BioResearch Group, College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea. Electronic address: parkjw@knu.ac.kr.
Jeen-Woo
JW
Park
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008268:Macular Degeneration / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D010070:Oxalates / Q000008:administration & dosage* / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism*; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism
D020533:Angiogenesis Inhibitors; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010070:Oxalates; D017382:Reactive Oxygen Species; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C015407:oxalomalic acid; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human
Oxalomalate; Reactive oxygen species; Retinal pigment epithelium; VEGF