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

Mahmoud, AM; Wilkinson, FL; Jones, AM; Wilkinson, JA; Romero, M; Duarte, J; Alexander, MY

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 tomimic 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 palmitateinduced
reactive oxygen species (ROS) production, lipid peroxidation, and activity and expression of NADPH oxidase.
These effectswere attributed to activation of the Nrf2/ARE pathway and downstreamactivation 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.

• Journal Article Type: Article
• Acceptance Date: Aug 19, 2016
• Online Publication Date: Aug 21, 2016
• Publication Date: Jan 1, 2017
• Deposit Date: Nov 10, 2016
• Publicly Available Date: Aug 21, 2017
• Journal: Biochimica et Biophysica Acta (BBA) - General Subjects
• Print ISSN: 0304-4165
• Publisher: Elsevier
• Volume: 1861
• Issue: 1.A
• Pages: 3311-3322
• DOI: https://doi.org/10.1016/j.bbagen.2016.08.013
• Publisher URL: http://dx.doi.org/10.1016/j.bbagen.2016.08.013
• Related Public URLs: http://www.sciencedirect.com/science/journal/03044165