Hypoxic preconditioning protection is eliminated in HIF-1α knockout mice subjected to neonatal hypoxia-ischemia
R Ann Sheldon1, Christina L Lee2, Xiangning Jiang1
11] Department of Pediatrics, University of California, San Francisco, San Francisco, California [2] Newborn Brain Research Institute, University of California, San Francisco, San Francisco, California.
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-1α). This study sought to clarify the role of HIF-1α after HPc and HI.
Methods:
To induce HPc, HIF-1α 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-1α, 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-1α knockout brain. In WT, HIF-1α increased after hypoxia and after HI, but not with HPc. The HIF-1α knockout showed no change in HIF-1α after hypoxia, HI, or HPc/HI. After HI, spectrin 145/150 was higher in HIF-1α 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-1α knockout.
Conclusion:
These results indicate that HIF-1α 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.
