Selenium, an essential trace element, is important to human health. Recently, supra-nutritional selenium intake was shown to be associated with an increased risk of type II diabetes and may therefore affect cardiovascular-disease risk, though the underpinning mechanisms are not clear. Some cancer studies reported that high selenium doses cause apoptosis through the induction of endoplasmic reticulum (ER) stress response. Because ER stress is also involved in the pathogenesis of insulin resistance and endothelial dysfunction (ED), which are implicated in the development of atherosclerosis, we hypothesised that supra-nutritional selenium intake could cause diabetes and ED through ER stress.
The Eahy.926 endothelial-cell line or human umbilical-vein endothelial cells (HUVECs) were treated with varying doses of selenite in the presence or absence of the chemical chaperone, 4-phenylbutryic acid (PBA), which inhibits ER stress. ER-stress activation was evaluated by qPCR. Apoptosis was assessed by flow cytometry, western blot and caspase 3/7 colorimetric assay. To assess endothelial function, we evaluated nitric-oxide (NO) release and eNOS activation.
In contrast to physiological concentrations of selenite, high doses enhanced mRNA expression of pro-apoptotic ER-stress markers e.g. activating transcription factor-4 and C/EBP homologous protein. High selenite doses also significantly decreased cell viability and increased apoptosis. Interestingly, these effects were significantly prevented in the presence of PBA, implicating ER-stress. Furthermore, we observed that ER stress induced by high selenite decreased NO production, indicating ED.
Overall, we show that supra-nutritional selenium doses activate ER-stress-mediated apoptosis in the endothelium, reducing the bioavailability of NO and causing ED, a hallmark of cardiovascular disease.
- CARDIAC PROCEDURES AND THERAPY
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