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.

Citation

Mahmoud, A., Wilkinson, F., Jones, A., Wilkinson, J., Romero, M., Duarte, J., & Alexander, M. (2017). A novel role for small molecule glycomimetics in the protection against lipid-induced endothelial dysfunction : Involvement of Akt/eNOS and Nrf2/ARE signaling. BBA - General Subjects, 1861(1.A), 3311-3322. https://doi.org/10.1016/j.bbagen.2016.08.013

• 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