Liver X Receptor Agonist Inhibits Oxidized Low-Density Lipoprotein Induced Choroidal Neovascularization via the NF-κB Signaling Pathway.

Age-related macular degeneration (AMD) is the most common blindness-causing disease among the elderly. Under oxidative stress, low-density lipoprotein in the outer layer of the retina is easily converted into oxidized low-density lipoprotein (OxLDL), which promotes the development of choroidal neovascularization (CNV), the main pathological change in wet AMD. Liver X receptor (LXR), a ligand-activated nuclear transcription factor, regulates various processes related to CNV, including lipid metabolism, cholesterol transport, inflammation, and angiogenesis. In this study, we evaluated the effects of the LXR agonist TO901317 (TO) on CNV. Our results demonstrated that the TO could inhibit OxLDL-induced CNV in mice as well as inflammation and angiogenesis in vitro. Using siRNA transfection in cells and Vldlr-/- mice, we further confirmed the inhibitory effects of TO against the inflammatory response and oxidative stress. Mechanistically, the LXR agonist reduces the inflammatory response via the nuclear translocation of NF-κB p65 in the pathway for NF-κB activation and by enhancing ABCG1-dependent lipid transportation. Therefore, an LXR agonist is a promising therapeutic candidate for AMD, especially for wet AMD.

OxLDL enhances choroidal neovascularization lesion through inducing vascular endothelium to mesenchymal transition process and angiogenic factor expression.

Oxidized lowdensity lipoprotein (OxLDL) can impact the formation of choroidal neovascularization (CNV) via regulating endothelial cell proliferation and secretion of inflammatory and angiogenic factors, but the specific molecular mechanism is not clear. In this study, we evaluated the role of molecular pathways that affect angiogenesis at different stages. In vivo, we found that intravitreal injection of OxLDL following the laser photocoagulation significantly enhanced the CNV size. In vitro experiment confirmed that OxLDL impacts the formation of CNV via regulating endothelial cell proliferation in Rhesus monkey choroid-retinal vascular endothelial cells (RF/6A) and secretion of inflammatory and angiogenic factors. OxLDL promotes angiogenesis through increasing VEGF and some other pro-angiogenic factors expression. Treatment with LY294002, a specific inhibitor of the PI3K pathway, could abrogate VEGF-increased angiogenesis. OxLDL induced the TGF-ß2/Smad signaling axis to participate in the maintenance of neovascular formation. Treatment with PD98059, a specific inhibitor of the MEK pathway, could abrogate it. We also found that OxLDL increased the level of pro-angiogenic factors and promoted the endothelium-mesenchymal transition (EndMT) process, which is important for early tube formation and late maintaining of angiogenesis respectively. In summary, our results indicate that OxLDL affects CNV formation by increasing VEGF expression in the early stage, with activation of the MEK/ERK pathway. And OxLDL induces the TGF-ß2/Smad signaling axis, which leads to EndMT, to affects the later stage of CNV formation by activating the PI3K/AKT pathway.