RT Journal Article
SR Electronic
T1 P31 Endoplasmic reticulum stress drives high selenium induced endothelial dysfunction
JF Heart
JO Heart
FD BMJ Publishing Group Ltd and British Cardiovascular Society
SP A11
OP A12
DO 10.1136/heartjnl-2016-310696.35
VO 102
IS Suppl 8
A1 M Zachariah
A1 H Maamoun
A1 L Milano
A1 LB Meira
A1 A Agouni
A1 MP Rayman
YR 2016
UL http://heart.bmj.com/content/102/Suppl_8/A11.4.abstract
AB 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.