Glycomimetics; A novel class of drugs to protect against free fatty nAcid-induced endothelial dysfunction

Research output: Contribution to journalAbstract

Standard

Glycomimetics; A novel class of drugs to protect against free fatty nAcid-induced endothelial dysfunction. / Wilkinson, Fiona l; Mahmoud, Ayman; Wilkinson, James; Romero, Miguel; Duarte, Juan; Yvonne Alexander, M; Jones, Alan.

In: Heart, Vol. 102, No. Suppl 6, 204, 01.06.2016, p. A136.

Research output: Contribution to journalAbstract

Harvard

Wilkinson, F, Mahmoud, A, Wilkinson, J, Romero, M, Duarte, J, Yvonne Alexander, M & Jones, A 2016, 'Glycomimetics; A novel class of drugs to protect against free fatty nAcid-induced endothelial dysfunction', Heart, vol. 102, no. Suppl 6, 204, pp. A136. https://doi.org/10.1136/heartjnl-2016-309890.204

APA

Wilkinson, F., Mahmoud, A., Wilkinson, J., Romero, M., Duarte, J., Yvonne Alexander, M., & Jones, A. (2016). Glycomimetics; A novel class of drugs to protect against free fatty nAcid-induced endothelial dysfunction. Heart, 102(Suppl 6), A136. [204]. https://doi.org/10.1136/heartjnl-2016-309890.204

Vancouver

Wilkinson F, Mahmoud A, Wilkinson J, Romero M, Duarte J, Yvonne Alexander M et al. Glycomimetics; A novel class of drugs to protect against free fatty nAcid-induced endothelial dysfunction. Heart. 2016 Jun 1;102(Suppl 6):A136. 204. https://doi.org/10.1136/heartjnl-2016-309890.204

Author

Wilkinson, Fiona l ; Mahmoud, Ayman ; Wilkinson, James ; Romero, Miguel ; Duarte, Juan ; Yvonne Alexander, M ; Jones, Alan. / Glycomimetics; A novel class of drugs to protect against free fatty nAcid-induced endothelial dysfunction. In: Heart. 2016 ; Vol. 102, No. Suppl 6. pp. A136.

Bibtex

@article{b12b758443d843a5a696719cdd67b39e,
title = "Glycomimetics; A novel class of drugs to protect against free fatty nAcid-induced endothelial dysfunction",
abstract = "Background Endothelial dysfunction is a key player in cardiovascular disease (CVD) complications and novel drugs are required to treat this pathological process. Glycosaminoglycans (GAGs) are key molecules that regulate signalling in many biological processes and drugs that mimic their structure could be a novel source of therapeutics to target specific CVD pathways.Purpose We have synthesised a set of four glycomimetic compounds and our objective was to determine whether they could activate protective pathways in endothelial cells subjected to fatty acid-induced endothelial dysfunction.Methods Glycomimetics, C1-C4, were synthesised by the stepwise transformation of 2,5-dihydroxybenzoic acid to a range of 2,5-substituted benzoic acid derivatives, incorporating the key sulphate groups to mimic heparan sulphate. Human Umbilical Vein Endothelial Cells (HUVECs) were treated with glycomimetics (1{\^A}µM) in the presence or absence of the free fatty acid, palmitate. DAF-2 and H2DCF-DA assays were used to determine NO and reactive oxygen species (ROS) production, respectively. Lipid peroxidation colorimetric and antioxidant enzyme activity ssays were also carried out. RT-PCR and western blotting were utilised to measure Akt, eNOS, Nrf-2, NQO-1 and HO-1 expression. Endothelial function was determined ex vivo using acetylcholine-induced endothelium-dependent relaxation in mouse thoracic aortic rings by wire myography.Results All four glycomimetics protected against palmitate-induced oxidative stress and enhanced NO production in vitro via upregulation of Akt/eNOS signalling, activation of the Nrf2/ARE pathway and down-regulation of ROS-induced lipid peroxidation. Under palmitate-induced oxidative stress, ex vivo endothelium-dependent relaxation was significantly enhanced by all four glycomimetics. Furthermore, the glycomimetics did not induce HUVEC activation, as determined by lack of ICAM-1 protein.Conclusion We have developed a new set of small molecule glycomimetics that do not activate ECs and protect against free fatty acid-induced endothelial dysfunction both in vitro and ex vivo. Future work will focus on developing the glycomimetics into drug-like therapies that target endothelial damage.",
author = "Fiona l Wilkinson and Ayman Mahmoud and James Wilkinson and Miguel Romero and Juan Duarte and {Yvonne Alexander}, M and Alan Jones",
year = "2016",
month = jun,
day = "1",
doi = "10.1136/heartjnl-2016-309890.204",
language = "English",
volume = "102",
pages = "A136",
journal = "Heart",
issn = "1355-6037",
publisher = "BMJ Publishing Group",
number = "Suppl 6",

}

RIS

TY - JOUR

T1 - Glycomimetics; A novel class of drugs to protect against free fatty nAcid-induced endothelial dysfunction

AU - Wilkinson, Fiona l

AU - Mahmoud, Ayman

AU - Wilkinson, James

AU - Romero, Miguel

AU - Duarte, Juan

AU - Yvonne Alexander, M

AU - Jones, Alan

PY - 2016/6/1

Y1 - 2016/6/1

N2 - Background Endothelial dysfunction is a key player in cardiovascular disease (CVD) complications and novel drugs are required to treat this pathological process. Glycosaminoglycans (GAGs) are key molecules that regulate signalling in many biological processes and drugs that mimic their structure could be a novel source of therapeutics to target specific CVD pathways.Purpose We have synthesised a set of four glycomimetic compounds and our objective was to determine whether they could activate protective pathways in endothelial cells subjected to fatty acid-induced endothelial dysfunction.Methods Glycomimetics, C1-C4, were synthesised by the stepwise transformation of 2,5-dihydroxybenzoic acid to a range of 2,5-substituted benzoic acid derivatives, incorporating the key sulphate groups to mimic heparan sulphate. Human Umbilical Vein Endothelial Cells (HUVECs) were treated with glycomimetics (1µM) in the presence or absence of the free fatty acid, palmitate. DAF-2 and H2DCF-DA assays were used to determine NO and reactive oxygen species (ROS) production, respectively. Lipid peroxidation colorimetric and antioxidant enzyme activity ssays were also carried out. RT-PCR and western blotting were utilised to measure Akt, eNOS, Nrf-2, NQO-1 and HO-1 expression. Endothelial function was determined ex vivo using acetylcholine-induced endothelium-dependent relaxation in mouse thoracic aortic rings by wire myography.Results All four glycomimetics protected against palmitate-induced oxidative stress and enhanced NO production in vitro via upregulation of Akt/eNOS signalling, activation of the Nrf2/ARE pathway and down-regulation of ROS-induced lipid peroxidation. Under palmitate-induced oxidative stress, ex vivo endothelium-dependent relaxation was significantly enhanced by all four glycomimetics. Furthermore, the glycomimetics did not induce HUVEC activation, as determined by lack of ICAM-1 protein.Conclusion We have developed a new set of small molecule glycomimetics that do not activate ECs and protect against free fatty acid-induced endothelial dysfunction both in vitro and ex vivo. Future work will focus on developing the glycomimetics into drug-like therapies that target endothelial damage.

AB - Background Endothelial dysfunction is a key player in cardiovascular disease (CVD) complications and novel drugs are required to treat this pathological process. Glycosaminoglycans (GAGs) are key molecules that regulate signalling in many biological processes and drugs that mimic their structure could be a novel source of therapeutics to target specific CVD pathways.Purpose We have synthesised a set of four glycomimetic compounds and our objective was to determine whether they could activate protective pathways in endothelial cells subjected to fatty acid-induced endothelial dysfunction.Methods Glycomimetics, C1-C4, were synthesised by the stepwise transformation of 2,5-dihydroxybenzoic acid to a range of 2,5-substituted benzoic acid derivatives, incorporating the key sulphate groups to mimic heparan sulphate. Human Umbilical Vein Endothelial Cells (HUVECs) were treated with glycomimetics (1µM) in the presence or absence of the free fatty acid, palmitate. DAF-2 and H2DCF-DA assays were used to determine NO and reactive oxygen species (ROS) production, respectively. Lipid peroxidation colorimetric and antioxidant enzyme activity ssays were also carried out. RT-PCR and western blotting were utilised to measure Akt, eNOS, Nrf-2, NQO-1 and HO-1 expression. Endothelial function was determined ex vivo using acetylcholine-induced endothelium-dependent relaxation in mouse thoracic aortic rings by wire myography.Results All four glycomimetics protected against palmitate-induced oxidative stress and enhanced NO production in vitro via upregulation of Akt/eNOS signalling, activation of the Nrf2/ARE pathway and down-regulation of ROS-induced lipid peroxidation. Under palmitate-induced oxidative stress, ex vivo endothelium-dependent relaxation was significantly enhanced by all four glycomimetics. Furthermore, the glycomimetics did not induce HUVEC activation, as determined by lack of ICAM-1 protein.Conclusion We have developed a new set of small molecule glycomimetics that do not activate ECs and protect against free fatty acid-induced endothelial dysfunction both in vitro and ex vivo. Future work will focus on developing the glycomimetics into drug-like therapies that target endothelial damage.

U2 - 10.1136/heartjnl-2016-309890.204

DO - 10.1136/heartjnl-2016-309890.204

M3 - Abstract

VL - 102

SP - A136

JO - Heart

JF - Heart

SN - 1355-6037

IS - Suppl 6

M1 - 204

ER -