Hypoxic preconditioning protection is eliminated in HIF-1 αknockout mice subjected to neonatal hypoxia ischemia

Abstract

Background:Hypoxic preconditioning (HPc) protects the neonatal brain in the setting of hypoxia-ischemia (HI). The mechanisms of protection may depend on activation of hypoxia-inducible factor (HIF-1). This study sought to clarify the role of HIF-1 after HPc and HI.Methods:To induce HPc, HIF-1 knockout and wild-type (WT) mice were exposed to hypoxia at postnatal day 6. At day 7, the mice underwent HI. Brain injury was determined by histology. HIF-1, downstream targets, and markers of cell death were measured by western blot.Results:HPc protected the WT brain compared with WT without HPc, but did not protect the HIF-1 knockout brain. In WT, HIF-1 increased after hypoxia and after HI, but not with HPc. The HIF-1 knockout showed no change in HIF-1 after hypoxia, HI, or HPc/HI. After HI, spectrin 145/150 was higher in HIF-1 knockout, but after HPc/HI, it was higher in WT. Lysosome-Associated membrane protein was higher in WT early after HI, but not later. After HPc/HI, lysosome-Associated membrane protein was higher in HIF-1 knockout.Conclusion:These results indicate that HIF-1 is necessary for HPc protection in the neonatal brain and may affect cell death after HI. Different death and repair mechanisms depend on the timing of HPc.Copyright © 2014 International Pediatric Research Foundation, Inc.