title: Potential role of IGF-I in hypoxia tolerance using a rat hypoxic-ischemic model: activation of hypoxia-inducible factor 1alpha.
abstract: Hypoxia preconditioning and subsequent tolerance to hypoxia-ischemia damage is a well-known phenomenon and has significant implications in clinical medicine. In this investigation, we tested the hypothesis that the transcriptional activation of IGF-I is one of the underlying mechanisms for hypoxia-induced neuroprotection. In a rodent model of hypoxia-ischemia, hypoxia preconditioning improved neuronal survival as demonstrated by decreased hypoxia-ischemia-induced neuronal apoptosis. To study the role of IGF-I in hypoxia tolerance, we used in situ hybridization to examine IGF-I mRNA distribution on adjacent tissue sections. In cerebral cortex and hippocampus, hypoxia preconditioning resulted in an increase in neuronal IGF-I mRNA levels with or without hypoxia-ischemia. To test its direct effects, we added IGF-I to primary neuronal culture under varying oxygen concentrations. As oxygen concentration decreased, neuronal survival also decreased, which could be reversed by IGF-I, especially at the lowest oxygen concentration. Interestingly, IGF-I treatment resulted in an activation of hypoxia-inducible factor 1alpha (HIF-1alpha), a master transcription factor for hypoxia-induced metabolic adaptation. To evaluate whether IGF-I transcriptional activation correlates with HIF-1alpha activity, we studied the time course of HIF-1alpha DNA binding activity in the same rat model of hypoxia-ischemia. After hypoxia-ischemia, there was an increase in HIF-1alpha DNA binding activity in cortical tissues, with the highest increase around 24 h. Like IGF-I mRNA levels, hypoxia preconditioning increased HIF-1alpha DNA binding activity alone or with subsequent hypoxia ischemia. Overall, our results suggest that IGF-I transcriptional activation is one of the metabolic adaptive responses to hypoxia, which is likely mediated by a direct activation of HIF-1alpha.
authors.affiliation: Riley Research, Rm. 208, 699 West Indiana University Medical Center, Indianapolis, IN 46202, USA.
authors.forename: Xinghe
authors.initials: X
authors.lastname: Wang
authors.forename: Jixian
authors.initials: J
authors.lastname: Deng
authors.forename: David W
authors.initials: DW
authors.lastname: Boyle
authors.forename: Jin
authors.initials: J
authors.lastname: Zhong
authors.forename: Wei-Hua
authors.initials: WH
authors.lastname: Lee
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D002470:Cell Survival; D017931:DNA Primers; D024202:Electrophoretic Mobility Shift Assay; D006624:Hippocampus / Q000473:pathology / Q000503:physiopathology; D000860:Hypoxia / Q000503:physiopathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D020925:Hypoxia-Ischemia, Brain / Q000503:physiopathology*; D017403:In Situ Hybridization; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013788:Thalamus / Q000473:pathology / Q000503:physiopathology; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D014157:Transcription Factors; D007334:Insulin-Like Growth Factor I