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. doi: 10.1016/j.bbagen.2016.08.013. Epub 2016 Aug 21.

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: Endothelial dysfunction; Glycomimetics; Heparan sulfate; Oxidative stress; Small molecule drug discovery.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidant Response Elements / genetics
  • Aorta / drug effects
  • Aorta / physiopathology
  • Cell Survival / drug effects
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / physiopathology*
  • Human Umbilical Vein Endothelial Cells / drug effects
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Lipids / toxicity*
  • Male
  • Mice, Inbred BALB C
  • Models, Biological
  • NADPH Oxidases / metabolism
  • NF-E2-Related Factor 2 / metabolism
  • Nitric Oxide / metabolism
  • Nitric Oxide Synthase Type III / metabolism
  • Oxidative Stress / drug effects
  • Palmitic Acid / pharmacology
  • Phosphorylation / drug effects
  • Polysaccharides / chemistry
  • Polysaccharides / pharmacology*
  • Protective Agents / chemistry
  • Protective Agents / pharmacology*
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Reactive Oxygen Species / metabolism
  • Signal Transduction / drug effects*
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Vasodilation / drug effects

Substances

  • Lipids
  • NF-E2-Related Factor 2
  • Polysaccharides
  • Protective Agents
  • RNA, Messenger
  • Reactive Oxygen Species
  • Small Molecule Libraries
  • Palmitic Acid
  • Nitric Oxide
  • Nitric Oxide Synthase Type III
  • NADPH Oxidases
  • Proto-Oncogene Proteins c-akt