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P31 Endoplasmic reticulum stress drives high selenium induced endothelial dysfunction
  1. M Zachariah,
  2. H Maamoun,
  3. L Milano,
  4. LB Meira,
  5. A Agouni,
  6. MP Rayman
  1. School of Biosciences and Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK


Selenium is associated with insulin resistance and may therefore affect endothelial function, increasing type II diabetes and its associated cardiovascular-disease risk. However the molecular mechanisms underpinning this association are not clear. High selenium doses cause apoptosis in cancer cells through the induction of the endoplasmic reticulum (ER) stress response, a mechanism implicated in the pathogenesis of insulin resistance and endothelial dysfunction (ED). Thus we hypothesised that high selenium intake could cause ED via ER stress induction.

Endothelial cells were treated with selenite (0.5–10 µM) in the presence or absence of the chemical chaperone, 4-phenylbutyric acid (PBA). Supra-nutritional concentrations (5–10 µM of selenite) but not physiological concentration (0.5 µM) of selenite induced expression of several pro-apoptotic ER stress markers; such as activating transcription factor-4 (ATF4) and X-binding box-1 (XBP–1). Griess assay showed that high selenite treatment (5–10 µM) reduced nitric oxide production. Moreover, high selenium induced the production of reactive oxygen species as shown by flow cytometry and impaired endothelial cell function as assessed by in-vitro angiogenesis assay. Interestingly, pre-incubation with PBA completely reversed these effects of high selenium suggesting ER stress drives the response to selenite.

Overall, we hereby show that high selenium causes endothelial dysfunction and cell death through the activation of ER stress. These results highlight the importance of a balanced selenium intake for maximal health benefits and prevention of cardiovascular disease. These findings also indicate that cancer patients supplemented with high amounts of selenium as part of their chemotherapeutic regimen should be monitored for cardiovascular disease risk.

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