Inhibitory effect of zinc on hypoxic HIF-I activation in astrocytes

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