RT Journal Article
T1 A novel role for small molecule glycomimetics in the protection against lipid-induced endothelial dysfunction: Involvement of Akt/eNOS and Nrf2/ARE signaling.
A1 Mahmoud, Ayman M
A1 Wilkinson, Fiona L
A1 Jones, Alan M
A1 Wilkinson, James A
A1 Romero, Miguel
A1 Duarte, Juan
A1 Alexander, M Yvonne
K1 Endothelial dysfunction
K1 Glycomimetics
K1 Heparan sulfate
K1 Oxidative stress
K1 Small molecule drug discovery
AB 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. 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. 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. 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.
PB Elsevier BV
SN 0304-4165
YR 2016
FD 2016-08-19
LK http://hdl.handle.net/10668/10387
UL http://hdl.handle.net/10668/10387
LA en
NO Mahmoud AM, Wilkinson FL, Jones AM, Wilkinson JA, Romero M, Duarte J, et al. 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.
DS RISalud
RD Apr 10, 2025