Cadmium blocks hypoxia‐inducible factor (HIF)‐1‐mediated response to hypoxia by stimulating the proteasome‐dependent degradation of HIF‐1α

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Abstract
Cadmium is a substantial industrial and environmental pollutant which seriously impairs erythropoiesis. Cd has been demonstrated to aggravate anemia by suppressing erythropoietin gene expression in anemic patients. As hypoxic induction of erythropoietin mRNA depends on a transcription factor, hypoxia-inducible factor 1 (HIF-1), we hypothesized that Cd suppresses the hypoxic activation of HIF-1. In hypoxic Hep3B cells, all mRNAs of various genes, which are known to be upregulated by HIF-1 activation under hypoxia, were suppressed by Cd in a dose-dependent manner. Cd inhibited the hypoxia-induced activity of luciferase in 293 cells which was transfected with a reporter plasmid carrying a hypoxia response element. By electrophoretic mobility gel shift assay, Cd inhibited the DNA-binding activity of HIF-1 in hypoxic Hep3B cells. Cd reduced the amount of HIF-1α protein in hypoxia, whereas it didn’t affect HIF-1 α mRNA levels. Moreover, Cd inhibited HIF-1α accumulation induced by cobalt and desferrioxamine. Antioxidants and a proteasome inhibitor prevented the HIF-1α degradation caused by Cd. The possibility that oxidative stress mediates this action of Cd was examined. Cd didn’t affect protein oxidation and reduced glutathione levels in hypoxic cells. These results indicate that Cd triggers a redox/proteasome-dependent degradation of HIF-1α protein, reducing HIF-1 activity and in turn suppressing the hypoxic induction of hypoxia-inducible genes.