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205 High Selenium Intake is Associated with Endothelial Dysfunction: Critical Role for Endoplasmic Reticulum Stress
  1. Matshediso Zachariah,
  2. Abdelali Agouni,
  3. Margaret P Rayman,
  4. Hatem Maamoun
  1. University of Surrey


Selenium is an essential trace element important to human health. Recently, supra-nutritional selenium intake was shown to be associated with insulin resistance and may therefore affect endothelial function increasing type II diabetes risk and associated cardiovascular-disease risk. However the underpinning molecular mechanisms involved are not clear. High selenium doses cause apoptosis in some cancer cells through the induction of endoplasmic reticulum (ER) stress response. ER stress is also a mechanism involved in the pathogenesis of insulin resistance and endothelial dysfunction (ED), which are implicated in the development of atherosclerosis, thus we hypothesised that high selenium intake could cause endothelial dysfunction through ER stress.

Endothelial cells were treated with 0.5–20 µM of selenite in the presence or absence of the chemical chaperone, 4-phenylbutryic acid (PBA), which increases ER homeostasis. ER stress activation was evaluated by qPCR. Endothelial dysfunction was then assessed by investigating nitric oxide (NO) production (Griess assay), reactive oxygen species (ROS) release (flow cytometry), eNOS activation (western blot), apoptosis (flow cytometry) and caspases 3/7 activity.

Treatment of cells with supra-nutritional concentrations of selenium (5–20 µM of selenite) compared to physiological concentration (0.5 µM) enhanced mRNA expression of several pro-apoptotic ER-stress markers; such as activating transcription factor-4 (ATF4) and CAAA/enhanced-binding homologous protein (CHOP). Interestingly, the pre-incubation of cells with chemical chaperone PBA completely reversed ER stress response mediated by high selenium treatment. In addition, high selenite treatment (5–20 µM) reduced NO production and enhanced ROS production indicating oxidative stress. Also, high selenium caused a decrease in the expression of active phosphorylated form of eNOS. The pre-treatment of cells with PBA significantly reduced high selenium-induced oxidative stress and enhanced eNOS phosphorylation. Finally, supra-nutritional concentrations of selenite also enhanced apoptosis and increased caspases 3/7 activity in endothelial cells compared to the physiological concentration. Importantly, pre-treatment of cells with PBA completely reversed high selenium-mediated cell death.

Overall, we show here that high selenium treatment causes endothelial dysfunction and cell death through the activation of ER stress response. These results highlight the importance of a balanced selenium intake in order to achieve maximal health benefits. These findings also underscore the importance to monitor cardiovascular risk development in cancer patients supplemented with high amounts of selenium as part of their chemotherapeutic intervention.

  • Endoplasmic Reticulum Stress
  • Endothelial Dysfunction
  • Selenium

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