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High selenium induces endothelial dysfunction via endoplasmic reticulum stress.

Zachariah, Matshediso (2017) High selenium induces endothelial dysfunction via endoplasmic reticulum stress. Doctoral thesis, University of Surrey.

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Abstract

Selenium (Se) is associated with insulin resistance and may affect endothelial function thereby increasing the risk of type 2 diabetes and associated cardiovascular disease (CVD). However, the molecular mechanisms involved are not clear. The endoplasmic-reticulum (ER) stress response is a mechanism involved in apoptosis induced by high Se in some cancer cells and, also in the pathogenesis of insulin resistance and endothelial dysfunction (ED). Thus, we hypothesised that high Se status causes ED through ER stress response. Endothelial cells (HUVECs) and EA.hy926 cell lines were treated with selenite (0.5-10 µM) for 24 hours in the presence or absence of the ER chemical chaperone, 4-phenylbutryic acid (PBA). ER stress markers were investigated using qPCR and western-blot technique. Endothelial function was assessed by the Griess assay, flow cytometry, Matrigel® and colourimetric assays. Data were expressed as S.E.M (p<0.05) vs. control. High Se concentration (5-10 µM) compared to physiological concentration (0.5–2.0 µM) enhanced mRNA expression of ER-stress markers:- activating transcription factor-4 (ATF4), CAAA/enhanced-binding homologous protein (CHOP) and X-binding box-1 (XBP-1). In addition, high selenite concentration reduced nitric oxide production and angiogenic capacity in endothelial cells. Moreover, high selenite treatment significantly (p<0.05) increased production of reactive oxygen species (ROS) and induced apoptosis through caspase-3/7 activity. Interestingly, PBA completely reversed all the effects of high selenite on endothelial function, indicating the involvement of the ER-stress response. High Se treatment caused endothelial dysfunction through the activation of the ER-stress response. This thesis additionally warns the public to be aware of the risks of the use of Se supplements as a prophylactic agent against oxidative-stress disease.

Item Type: Thesis (Doctoral)
Divisions : Theses
Authors :
NameEmailORCID
Zachariah, MatshedisoUNSPECIFIEDUNSPECIFIED
Date : 21 December 2017
Funders : University of Botswana and Government of Botswana
Contributors :
ContributionNameEmailORCID
http://www.loc.gov/loc.terms/relators/THSRayman, MargaretM.Rayman@surrey.ac.ukUNSPECIFIED
http://www.loc.gov/loc.terms/relators/THSMeira, LisianeL.Meira@surrey.ac.ukUNSPECIFIED
http://www.loc.gov/loc.terms/relators/THSAgouni, Abdelalia.agouni@surrey.ac.ukUNSPECIFIED
Depositing User : Matshediso Zachariah
Date Deposited : 08 Jan 2018 09:34
Last Modified : 08 Jan 2018 09:34
URI: http://epubs.surrey.ac.uk/id/eprint/845246

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