Inhibitory effect of zinc on hypoxic HIF-1 activation in astrocytes.

Hypoxia-inducible factor-1 (HIF-1) regulates the expression of neuroprotective genes such as erythropoietin (EPO). We investigated the mechanism by which zinc, an excitotoxin-like metal, regulates HIF-1 under hypoxic conditions in astrocytes. In hypoxic LN215 cells, HIF-1alpha stabilized and accumulated in the nucleus, resulting in an increase in its DNA-binding activity to the EPO enhancer. Zinc inhibited hypoxia-induced increases in HIF-1 DNA-binding activity and the HIF-1-dependent mRNA expression of EPO. Zinc did not affect hypoxic stabilization of HIF-1alpha. Nuclear migration of HIF-1alpha upon hypoxia was reduced by zinc. Complete blockade of hypoxia-induced assembly of HIF-1alpha-HIF-1beta complex was observed after treatment of zinc. These findings suggest that zinc hampers hypoxia-stimulated HIF-1 activation in astrocytes by inhibiting nuclear HIF-1alpha translocation and subsequently disrupting HIF-1 heterodimerization.