title: A novel role for small molecule glycomimetics in the protection against lipid-induced endothelial dysfunction: Involvement of Akt/eNOS and Nrf2/ARE signaling.
abstract: Glycomimetics 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.
authors.affiliation: Cardiovascular Research Group, Healthcare Science Research Centre & Manchester Academic Health Science Centre, Faculty of Science and Engineering, Manchester Metropolitan University, UK; Physiology Division, Department of Zoology, Faculty of Science, Beni-Suef University, Egypt.
authors.forename: Ayman M
authors.initials: AM
authors.lastname: Mahmoud
authors.affiliation: Cardiovascular Research Group, Healthcare Science Research Centre & Manchester Academic Health Science Centre, Faculty of Science and Engineering, Manchester Metropolitan University, UK.
authors.forename: Fiona L
authors.initials: FL
authors.lastname: Wilkinson
authors.affiliation: Division of Chemistry and Environmental Science, Faculty of Science and Engineering, Manchester Metropolitan University, UK.
authors.forename: Alan M
authors.initials: AM
authors.lastname: Jones
authors.affiliation: Centre for Molecular Drug Design, University of Salford, UK.
authors.forename: James A
authors.initials: JA
authors.lastname: Wilkinson
authors.affiliation: Department of Pharmacology, School of Pharmacy, University of Granada, & Instituto de Investigación Biosanitaria de Granada (Ibs.GRANADA), Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Romero
authors.affiliation: Department of Pharmacology, School of Pharmacy, University of Granada, & Instituto de Investigación Biosanitaria de Granada (Ibs.GRANADA), Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Duarte
authors.affiliation: Cardiovascular Research Group, Healthcare Science Research Centre & Manchester Academic Health Science Centre, Faculty of Science and Engineering, Manchester Metropolitan University, UK. Electronic address: y.alexander@mmu.ac.uk.
authors.forename: M Yvonne
authors.initials: MY
authors.lastname: Alexander
mesh_terms: D000818:Animals; D061745:Antioxidant Response Elements / Q000235:genetics; D001011:Aorta / Q000187:drug effects / Q000503:physiopathology; D002470:Cell Survival / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D008055:Lipids / Q000633:toxicity*; D008297:Male; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D019255:NADPH Oxidases / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D019308:Palmitic Acid / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011134:Polysaccharides / Q000737:chemistry / Q000494:pharmacology*; D020011:Protective Agents / Q000737:chemistry / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects
chemical_list: D008055:Lipids; D051267:NF-E2-Related Factor 2; D011134:Polysaccharides; D020011:Protective Agents; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D054852:Small Molecule Libraries; D019308:Palmitic Acid; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D019255:NADPH Oxidases; D051057:Proto-Oncogene Proteins c-akt
keywords: Endothelial dysfunction; Glycomimetics; Heparan sulfate; Oxidative stress; Small molecule drug discovery