The glutathione mimic ebselen inhibits oxidative stress but not endoplasmic reticulum stress in endothelial cells.

Abstract

AIMS:

Reactive oxygen species are associated with cardiovascular disease, diabetes, and atherosclerosis, yet the use of antioxidants in clinical trials has been ineffective at improving outcomes. In endothelial cells, high-dextrose-induced oxidative stress and endoplasmic reticulum stress promote endothelial dysfunction leading to the recruitment and activation of peripheral blood lymphocytes and the breakdown of barrier function. Ebselen, a glutathione peroxidase 1 (GPX1) mimic, has been shown to improve β-cell function in diabetes and prevent atherosclerosis.

MAIN METHODS:

To determine if ebselen inhibits both oxidative stress and endoplasmic reticulum (ER) stress in endothelial cells, we examined its effects in human umbilical vein endothelial cells (HUVEC) and human coronary artery endothelial cells (HCAEC) with and without high-dextrose. Oxidative stress and ER stress were measured by 2-methyl-6-(4-methoxyphenyl)-3,7-dihydroimidazo[1,2-A]pyrazin-3-one hydrochloride chemiluminescence and ER stress alkaline phosphatase assays, respectively. GPX1 over-expression and knockdown were performed by transfecting cells with a GPX1 expression construct or a GPX1-specific siRNA, respectively.

KEY FINDINGS:

Ebselen inhibited dextrose-induced oxidative stress but not ER stress in both HUVEC and HCAEC. Ebselen also had no effect on tunicamycin-induced ER stress in HCAEC. Furthermore, augmentation of GPX1 activity directly by sodium selenite supplementation or transfection of a GPX1 expression plasmid decreased dextrose-induced oxidative stress but not ER stress, while GPX1 knockout enhanced oxidative stress but had no effect on ER stress.

SIGNIFICANCE:

These results suggest that ebselen targets only oxidative stress but not ER stress.

• Authors: Salma Makhoul Ahwach, Melanie Thomas, Luisa Onstead-Haas, Arshag D Mooradian, Michael J Haas
• Journal: Life sciences (Life Sci) Vol. 134 Pg. 9-15 (Aug 01 2015) ISSN: 1879-0631 [Electronic] Netherlands
• PMID: 26006036 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015. Published by Elsevier Inc.

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Azoles
• Isoindoles
• Organoselenium Compounds
• Trace Elements
• ebselen
• Glutathione Peroxidase
• Glutathione
• Sodium Selenite
• Glutathione Peroxidase GPX1
• GPX1 protein, human

Topics

• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Azoles (pharmacology)
• Biomimetic Materials (pharmacology)
• Endoplasmic Reticulum Stress (drug effects)
• Glutathione
• Glutathione Peroxidase (metabolism)
• Human Umbilical Vein Endothelial Cells (metabolism)
• Humans
• Isoindoles
• Organoselenium Compounds (pharmacology)
• Oxidative Stress (drug effects)
• Sodium Selenite (pharmacology)
• Trace Elements (pharmacology)
• Glutathione Peroxidase GPX1