Impaired expression of neuroprotective molecules in the HIF-1alpha pathway following traumatic brain injury in aged mice.
Elderly traumatic brain injury (TBI) patients have higher rates of mortality and worse functional outcome than non-elderly TBI patients. The mechanisms involved in poor outcomes in the elderly are not well understood. Hypoxia-inducible factor-1 alpha (HIF-1alpha) is a basic helix-loop-helix transcription factor that modulates expression of key genes involved in neuroprotection. In this study, we studied the expression of HIF-1alpha and its target survival genes, heme oxygenase-1 (HO-1), vascular endothelial growth factor (VEGF), and erythropoietin (EPO) in the brains of adult versus aged mice following controlled cortical impact (CCI) injury. Adult (5-6 months) and aged (23-24 months) C57Bl/6 mice were injured using a CCI device. At 72 h post-injury, mice were sacrificed and the injured cortex was used for mRNA and protein analysis using real-time reverse transcription--polymerase chain reaction (RT-PCR) and Western blotting protocols. Following injury, HIF-1alpha, HO-1, and VEGF showed upregulation in both the young and aged mice, but in the aged animals the increase in HIF-1alpha and VEGF in response to injury was much lower than in the adult injured animals. EPO was upregulated in the adult injured brain, but not in the aged injured brain. These results support the hypothesis that reduced expression of genes in the HIF-1alpha neuroprotective pathway in aging may contribute to poor prognosis in the elderly following TBI.
Anderson
Joshua
J
Steve Palermo Nerve Regeneration Laboratory, University of Kansas Medical Center, Kansas City, Kansas, USA.
Sandhir
Rajat
R
Hamilton
Eric S
ES
Berman
Nancy E J
NE
D000375:Aging / Q000502:physiology*; D000818:Animals; D015153:Blotting, Western; D001930:Brain Injuries / Q000235:genetics / Q000378:metabolism*; D004921:Erythropoietin / Q000096:biosynthesis / Q000235:genetics; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000096:biosynthesis / Q000235:genetics; D051547:Heme Oxygenase-1 / Q000096:biosynthesis / Q000235:genetics; D002534:Hypoxia, Brain / Q000378:metabolism / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics
C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D004921:Erythropoietin; D051547:Heme Oxygenase-1; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases