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

• Published in: Biochimica et biophysica acta. General subjects Vol. 1861; no. 1; pp. 3311 - 3322
• Main Authors: Mahmoud, Ayman M., Wilkinson, Fiona L., Jones, Alan M., Wilkinson, James A., Romero, Miguel, Duarte, Juan, Alexander, M. Yvonne
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.01.2017
• Subjects: 2,5-dihydroxybenzoic acid; Animals; Antioxidant Response Elements - genetics; Aorta - drug effects; Aorta - physiopathology; cardiovascular diseases; Cell Survival - drug effects; drugs; Endothelial dysfunction; endothelial nitric oxide synthase; Endothelium, Vascular - drug effects; Endothelium, Vascular - physiopathology; Glycomimetics; glycosaminoglycans; Heparan sulfate; human umbilical vein endothelial cells; Human Umbilical Vein Endothelial Cells - drug effects; Human Umbilical Vein Endothelial Cells - metabolism; lipid peroxidation; Lipids - toxicity; Male; mice; Mice, Inbred BALB C; Models, Biological; NAD(P)H oxidase (H2O2-forming); NADP (coenzyme); NADPH Oxidases - metabolism; NF-E2-Related Factor 2 - metabolism; nitric oxide; Nitric Oxide - metabolism; Nitric Oxide Synthase Type III - metabolism; Oxidative stress; Oxidative Stress - drug effects; palmitic acid; Palmitic Acid - pharmacology; Phosphorylation - drug effects; Polysaccharides - chemistry; Polysaccharides - pharmacology; Protective Agents - chemistry; Protective Agents - pharmacology; protective effect; proteins; Proto-Oncogene Proteins c-akt - metabolism; reactive oxygen species; Reactive Oxygen Species - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; signal transduction; Signal Transduction - drug effects; Small molecule drug discovery; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; sugars; sulfates; therapeutics; Vasodilation - drug effects; Heparan sulfate; Endothelial dysfunction; Glycomimetics; Oxidative stress; Small molecule drug discovery
• ISSN: 0304-4165; 1872-8006
• DOI: 10.1016/j.bbagen.2016.08.013

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. [Display omitted] •Small molecule glycomimetics protect against endothelial dysfunction.•Glycomimetics up-regulate Akt/eNOS signaling and restore nitric oxide bioavailability.•Glycomimetics reduce oxidative stress via activation of Nrf2/ARE signaling.•Glycomimetics improve endothelium-dependent relaxation and decrease ROS production and NADPH oxidase activity.