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 and Alexander, MY 2016, 'A novel role for small molecule glycomimetics in the protection against lipid-induced endothelial dysfunction: Involvement of Akt/eNOS and Nrf2/ARE signaling' , Biochimica et Biophysica Acta (BBA) - General Subjects .

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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.

Item Type: Article
Schools: Schools > School of Environment and Life Sciences
Journal or Publication Title: Biochimica et Biophysica Acta (BBA) - General Subjects
Publisher: Elsevier
ISSN: 0304-4165
Related URLs:
Funders: Non funded research
Depositing User: JA Wilkinson
Date Deposited: 10 Nov 2016 08:28
Last Modified: 19 Oct 2017 15:00
URI: http://usir.salford.ac.uk/id/eprint/40717

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