Role of hypoxia-inducible factor-1 in hypoxia-induced ischemic tolerance in neonatal rat brain

Abstract

Hypoxia‐inducible factor‐1 (HIF‐1) is a heterodimer composed of HIF‐1α and HIF‐1β protein subunits. This transcription factor is essential for the activation of hypoxia‐inducible genes like erythropoietin, some glucose transporters, the glycolytic enzymes, and vascular endothelial growth factor. Because HIF‐1 activation may promote cell survival in hypoxic tissues, we studied the effect of hypoxic preconditioning on HIF‐1 expression in neonatal rat brain. Hypoxic preconditioning (8% O₂ for 3 hours), a treatment known to protect the newborn rat brain against hypoxic‐ischemic injury, markedly increased HIF‐1α and HIF‐1β expression. To support the role of HIF‐1 in protective preconditioning, we also studied the effect of two other known HIF‐1 inducers, cobalt chloride (CoCl₂) and desferrioxamine (DFX), on HIF‐1 expression and neuroprotection in newborn brain. HIF‐1α and HIF‐1β protein levels were markedly increased after intraperitoneal injection of CoCl₂ (60 mg/kg) and moderately increased after intraperitoneal injection of DFX (200 mg/kg) 1 to 3 hours after the injections. Preconditioning with CoCl₂ or DFX 24 hours before hypoxia‐ischemia afforded 75 and 56% brain protection, respectively, compared with that in vehicle‐injected littermate controls. Thus, HIF‐1 activation could contribute to protective brain preconditioning, which could be used in high‐risk deliveries and other clinical situations. Ann Neurol 2000;48:285–296