Hypoxic preconditioning protection is eliminated in HIF-1α knockout mice subjected to neonatal hypoxia-ischemia.
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.


CONCLUSIONS
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.
1] Department of Pediatrics, University of California, San Francisco, San Francisco, California [2] Newborn Brain Research Institute, University of California, San Francisco, San Francisco, California.
R Ann
RA
Sheldon
Department of Pediatrics, University of California, San Francisco, San Francisco, California.
Christina L
CL
Lee
1] Department of Pediatrics, University of California, San Francisco, San Francisco, California [2] Newborn Brain Research Institute, University of California, San Francisco, San Francisco, California.
Xiangning
X
Jiang
Department of Pediatrics, University of California, San Francisco, San Francisco, California.
Renatta N
RN
Knox
1] Department of Pediatrics, University of California, San Francisco, San Francisco, California [2] Newborn Brain Research Institute, University of California, San Francisco, San Francisco, California [3] Department of Neurology, University of California, San Francisco, San Francisco, California.
Donna M
DM
Ferriero
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D001930:Brain Injuries / Q000378:metabolism; D016923:Cell Death; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005838:Genotype; D000860:Hypoxia / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics*; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism*; D019194:Ischemic Preconditioning; D051907:Lysosomal Membrane Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D013049:Spectrin / Q000378:metabolism; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051907:Lysosomal Membrane Proteins; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D013049:Spectrin; D048049:Extracellular Signal-Regulated MAP Kinases