Mahmoud, Ayman MWilkinson, Fiona LJones, Alan MWilkinson, James ARomero, MiguelDuarte, JuanAlexander, M Yvonne2023-01-252023-01-252016-08-19Mahmoud AM, Wilkinson FL, Jones AM, Wilkinson JA, Romero M, Duarte J, et al. A novel role for small molecule glycomimetics in the protection against lipid-induced endothelial dysfunction: Involvement of Akt/eNOS and Nrf2/ARE signaling. Biochim Biophys Acta Gen Subj. 2017 Jan;1861(1 Pt A):3311-3322.0304-4165http://hdl.handle.net/10668/10387Glycomimetics are a diverse array of saccharide-inspired compounds, designed to mimic the bioactive functions of glycosaminoglycans. Therefore, glycomimetics represent a unique source of novel therapies to target aberrant signaling and protein interactions in a wide range of diseases. We investigated the protective effects of four newly synthesized small molecule glycomimetics against lipid-induced endothelial dysfunction, with an emphasis on nitric oxide (NO) and oxidative stress. Four aromatic sugar mimetics were synthesized by the stepwise transformation of 2,5-dihydroxybenzoic acid to derivatives (C1-C4) incorporating sulfate groups to mimic the structure of heparan sulfate. Glycomimetic-treated human umbilical vein endothelial cells (HUVECs) were exposed to palmitic acid to model lipid-induced oxidative stress. Palmitate-induced impairment of NO production was restored by the glycomimetics, through activation of Akt/eNOS signaling. Furthermore, C1-C4 significantly inhibited palmitate-induced reactive oxygen species (ROS) production, lipid peroxidation, and activity and expression of NADPH oxidase. These effects were attributed to activation of the Nrf2/ARE pathway and downstream activation of cellular antioxidant and cytoprotective proteins. In ex vivo vascular reactivity studies, the glycomimetics (C1-C4) also demonstrated a significant improvement in endothelium-dependent relaxation and decreased ROS production and NADPH oxidase activity in isolated mouse thoracic aortic rings exposed to palmitate. The small molecule glycomimetics, C1-C4, protect against lipid-induced endothelial dysfunction through up-regulation of Akt/eNOS and Nrf2/ARE signaling pathways. Thus, carbohydrate-derived therapeutics are a new class of glycomimetic drugs targeting endothelial dysfunction, regarded as the first line of defense against vascular complications in cardiovascular disease.enEndothelial dysfunctionGlycomimeticsHeparan sulfateOxidative stressSmall molecule drug discoveryAnimalsAntioxidant Response ElementsAortaCell SurvivalEndothelium, VascularHuman Umbilical Vein Endothelial CellsLipidsMaleMice, Inbred BALB CModels, BiologicalNADPH OxidasesNF-E2-Related Factor 2Nitric OxideNitric Oxide Synthase Type IIIOxidative StressPalmitic AcidPhosphorylationPolysaccharidesProtective AgentsProto-Oncogene Proteins c-aktRNA, MessengerReactive Oxygen SpeciesSignal TransductionSmall Molecule LibrariesVasodilationresearch article27554845Restricted AccessARN MensajeroCélulas endoteliales de la vena umbilical humanaElementos de respuesta antioxidanteEndotelio vascularEspecies reactivas de oxígenoFactor 2 relacionado con NF-E2Estrés oxidativoFosforilaciónModelos biológicosNADPH OxidasasPolisacáridos Proteínas Proto-Oncogénicas c-aktÁcido PalmíticoTransducción de señal10.1016/j.bbagen.2016.08.013https://e-space.mmu.ac.uk/617078/3/Manuscript%20BBA-R1%20%282%29.pdf