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15 Mitochondrial toxicity of arsenite in human primary vascular endothelial cells
  1. Q Malik,
  2. K E Herbert
  1. Department of Cardiovascular Sciences, University of Leicester, Clinical Sciences Wing, Glenfield General Hospital, Leicester, UK

Abstract

Chronic inorganic arsenic exposure through consumption of contaminated drinking water promotes atherosclerosis. Although the pathogenesis is unclear, initiation is likely to involve damage to endothelium. Mitochondria are targets for inorganic arsenite in a variety of cell types including endothelial cells. We hypothesise that arsenite alters mitochondrial function leading to altered mitochondrial-mediated signalling and downstream endothelial dysfunction. The aim of this study was to investigate the effects of arsenite on mitochondrial bioenergetics and the subsequent effects on mitochondrial and nuclear DNA damage. Mitochondrial effects of arsenite were investigated in human umbilical vein endothelial cells (HUVECs) using the Seahorse extracellular flux analyser. This showed a dose-dependent decrease in the mitochondrial reserve capacity after 1–4-h exposure to 1–8 μM arsenite, limiting the capability of mitochondria to protect the cell against stress. Furthermore, a dose dependent decrease in the maximum oxygen consumption rate of the mitochondria was also observed, with an increase in non-mitochondrial oxygen consumption. At similar doses of arsenite, 24-h exposure resulted in a dose-dependent increase in nuclear DNA strand breaks in HUVECs measured using the Comet assay. Taken together with literature reports that arsenite concentrations of 5 μM and above induces reactive oxygen species generation in HUVEC, our data provide support to the hypothesis that mitochondria are early targets for arsenite in endothelial cells.

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