A novel role for small molecule glycomimetics in the protection against lipid-induced endothelial dysfunction: Involvement of Akt/eNOS and Nrf2/ARE signaling

Research output: Contribution to journalArticle

Authors

  • Ayman M. Mahmoud
  • James A. Wilkinson
  • Miguel Romero
  • Juan Duarte
  • M. Yvonne Alexander

Colleges, School and Institutes

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.

Details

Original languageEnglish
Pages (from-to)3311-3322
Number of pages12
JournalBiochimica et Biophysica Acta (BBA) - General Subjects
Volume1861
Issue number1
Early online date21 Aug 2016
Publication statusPublished - 1 Jan 2017

Keywords

  • Endothelial dysfunction, Glycomimetics, Heparan sulfate, Oxidative stress, Small molecule drug discovery