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

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-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.

Study of oxygen tension variation within live tumor spheroids using microfluidic devices and multi-photon laser scanning microscopy

“…In previous studies, low oxygen tension within spheroids is shown to play a key role in tumor progression and promotion of angiogenetic cytokines like stromal cell derived factor (SDF), IL-1β, TNF-α and vascular endothelial growth factor (VEGF). 57–60 In addition, the oxygenation is also found to be improved by influence of endothelial cells, 61 which agrees with the observation in the experiments.…”

IL-10 inhibits retinal pigment epithelium cell proliferation and migration through regulation of VEGF in rhegmatogenous retinal detachment

“…VEGF may promote cell proliferation, differentiation, migration and movement by increasing the permeability of blood vessels and degradation of extracellular matrix (35). VEGF upregulation may promote blood vessel growth, facilitate inflammatory factors secretion and aggravate inflammation, leading to damage of vascular integrity (36). In the present study, a significant reduction in the expression levels of VEGF mRNA and protein in RPE cells was observed following IL-10 treatment, which suggested that IL-10 may inhibit angiogenesis through the downregulation of VEGF expression.…”

Taurine Attenuates Calpain‐2 Induction and a Series of Cell Damage via Suppression of NOX‐Derived ROS in ARPE‐19 Cells

“…RPE cells are highly metabolically active cells that are located in the retina and play a vital role in maintaining normal visual function. Hence, RPE cells are vulnerable to oxidative stress [ 7 , 39 ]. In addition, sunlight is one of the causes for ROS production that can damage RPE cells [ 40 , 41 ].…”