Ayman M Mahmoud1, Fiona L Wilkinson2, Alan M Jones3, James A Wilkinson4, Miguel Romero5, Juan Duarte5, M Yvonne Alexander6. 1. Cardiovascular Research Group, Healthcare Science Research Centre & Manchester Academic Health Science Centre, Faculty of Science and Engineering, Manchester Metropolitan University, UK; Physiology Division, Department of Zoology, Faculty of Science, Beni-Suef University, Egypt. 2. Cardiovascular Research Group, Healthcare Science Research Centre & Manchester Academic Health Science Centre, Faculty of Science and Engineering, Manchester Metropolitan University, UK. 3. Division of Chemistry and Environmental Science, Faculty of Science and Engineering, Manchester Metropolitan University, UK. 4. Centre for Molecular Drug Design, University of Salford, UK. 5. Department of Pharmacology, School of Pharmacy, University of Granada, & Instituto de Investigación Biosanitaria de Granada (Ibs.GRANADA), Spain. 6. Cardiovascular Research Group, Healthcare Science Research Centre & Manchester Academic Health Science Centre, Faculty of Science and Engineering, Manchester Metropolitan University, UK. Electronic address: y.alexander@mmu.ac.uk.
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 to mimic 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 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. 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. Copyright Â
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 to mimic 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 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. 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. Copyright Â
Authors: Ayman M Mahmoud; Fiona L Wilkinson; Eoghan M McCarthy; Daniel Moreno-Martinez; Alexander Langford-Smith; Miguel Romero; Juan Duarte; M Yvonne Alexander Journal: FASEB J Date: 2017-07-07 Impact factor: 5.191
Authors: Ayman M Mahmoud; Sultan Alqahtani; Sarah I Othman; Mousa O Germoush; Omnia E Hussein; Gadh Al-Basher; Jong Seong Khim; Maha A Al-Qaraawi; Hanan M Al-Harbi; Abdulmannan Fadel; Ahmed A Allam Journal: Oxid Med Cell Longev Date: 2017-06-28 Impact factor: 6.543
Authors: Alexander W W Langford-Smith; Ahmad Hasan; Ria Weston; Nicola Edwards; Alan M Jones; Andrew J M Boulton; Frank L Bowling; S Tawqeer Rashid; Fiona L Wilkinson; M Yvonne Alexander Journal: Sci Rep Date: 2019-02-19 Impact factor: 4.379
Authors: Sandro Satta; Ayman M Mahmoud; Fiona L Wilkinson; M Yvonne Alexander; Stephen J White Journal: Oxid Med Cell Longev Date: 2017-09-14 Impact factor: 6.543
Authors: Ayman M Mahmoud; M Yvonne Alexander; Yusuf Tutar; Fiona L Wilkinson; Alessandro Venditti Journal: Oxid Med Cell Longev Date: 2017-11-19 Impact factor: 6.543
Authors: Rosario Jimenez; Marta Toral; Manuel Gómez-Guzmán; Miguel Romero; Manuel Sanchez; Ayman M Mahmoud; Juan Duarte Journal: Oxid Med Cell Longev Date: 2018-06-25 Impact factor: 6.543