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43 A novel role for small molecule glycomimetics in the protection against lipid-induced endothelial dysfunction
  1. Ayman M Mahmoud1,2,
  2. Fiona L Wilkinson1,
  3. Alan M Jones3,
  4. James A Wilkinson4,
  5. Miguel Romero5,
  6. Juan Duarte5,
  7. M Yvonne Alexander1
  1. 1Cardiovascular Research Group, Healthcare Science Research Centre
  2. 2Physiology Division, Department of Zoology, Faculty of Science, Beni-Suef University, Egypt
  3. 3Division of Chemistry and Environmental Science, Faculty of Science and Engineering, Manchester Metropolitan University, and Manchester Academic Health Science Centre, UK
  4. 4Centre for Molecular Drug Design, University of Salford, UK
  5. 5Department of Pharmacology, School of Pharmacy, University of Granada, and Instituto de Investigación Biosanitaria de Granada (Ibs. GRANADA), Spain

Abstract

Glycomimetics are molecules that mimic the structure of carbohydrates involved in important biological processes. Small molecule glycomimetics are an untapped source of novel therapies for endothelial dysfunction, a hallmark of cardiovascular complications associated with diabetes. The current study aims to investigate the possible protective effects of newly synthesised small molecule glycomimetics against lipid-induced endothelial dysfunction, with an emphasis on nitric oxide (NO) and induced oxidative stress. Glycomimetics were synthesised by the stepwise transformation of 2,5-dihydroxybenzoic acid to a range of 2,5-substituted benzoic acid derivatives incorporating the key sulfate groups to mimic the interactions of heparan sulfate. Acetylcholine-induced endothelium-dependent relaxation in mouse thoracic aortic rings was measured using wire myography, and human umbilical vein endothelial cells (HUVECs) function was assessed in the presence or absence of palmitate, with or without the test glycomimetics. NO and reactive oxygen species (ROS) production was measured using DAF-2 and H2DCF-DA, respectively. Colorimetric assays were used to determine lipid peroxidation and activity of the antioxidant enzymes. Expression of Akt, eNOS, Nrf-2, NQO-1 and HO-1 were assessed using RT-PCR and western blotting. At 1 µM concentration, the synthesised glycomimetics significantly improved endothelium-dependent relaxation ex vivo and protected HUVECs against palmitate-induced oxidative stress and reduced NO production. Pre-incubation of HUVECs with all compounds upregulated Akt/eNOS signalling, activated Nrf2/ARE pathway, and suppressed ROS-induced lipid peroxidation. In conclusion, our newly synthesised small molecule glycomimetics protect against lipid-induced endothelial dysfunction. These novel cytoprotective effects open the door to a new class of therapeutic drugs to target endothelial dysfunction.

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