The role and regulation of hypoxia-inducible factor-1α expression in brain development and neonatal hypoxic–ischemic brain injury

Fan, Xiyong, Heijnen, Cobi J., van der Kooij, Michael A., Groenendaal, Floris and van Bel, Floris (2009) The role and regulation of hypoxia-inducible factor-1α expression in brain development and neonatal hypoxic–ischemic brain injury. Brain Research Reviews, 62 1: 99-108. doi:10.1016/j.brainresrev.2009.09.006


Author Fan, Xiyong
Heijnen, Cobi J.
van der Kooij, Michael A.
Groenendaal, Floris
van Bel, Floris
Title The role and regulation of hypoxia-inducible factor-1α expression in brain development and neonatal hypoxic–ischemic brain injury
Journal name Brain Research Reviews   Check publisher's open access policy
ISSN 0165-0173
1872-6321
Publication date 2009-12-11
Sub-type Critical review of research, literature review, critical commentary
DOI 10.1016/j.brainresrev.2009.09.006
Open Access Status DOI
Volume 62
Issue 1
Start page 99
End page 108
Total pages 10
Place of publication Amsterdam, Netherlands
Publisher Elsevier BV
Language eng
Abstract During neonatal hypoxic–ischemic brain injury, activation of transcription of a series of genes is induced to stimulate erythropoiesis, anti-apoptosis, apoptosis, necrosis and angiogenesis. A key factor mediating these gene transcriptions is hypoxia-inducible factor-1α (HIF-1α). During hypoxia, HIF-1α protein is stabilized and heterodimerizes with HIF-1β to form HIF-1, subsequently regulating the expression of target genes. HIF-1α participates in early brain development and proliferation of neuronal precursor cells. Under pathological conditions, HIF-1α is known to play an important role in neonatal hypoxic–ischemic brain injury: on the one hand, HIF-1α has neuroprotective effects whereas it can also have neurotoxic effects. HIF-1α regulates the transcription of erythropoietin (EPO), which induces several pathways associated with neuroprotection. HIF-1α also promotes the expression of vascular endothelial cell growth factor (VEGF), which is related to neovascularization in hypoxic–ischemic brain areas. In addition, HIF-1α has an anti-apoptotic effect by increasing the expression of anti-apoptotic factors such as EPO during mild hypoxia. The neurotoxic effects of HIF-1α are represented by its participation in the apoptotic process by increasing the stability of the tumor suppressor protein p53 during severe hypoxia. Moreover, HIF-1α plays a role in cell necrosis, by interacting with calcium and calpain. HIF-1α can also exacerbate brain edema via increasing the permeability of the blood–brain barrier (BBB). Given these properties, HIF-1α has both neuroprotective and neurotoxic effects after hypoxia–ischemia. These events are cell type specific and related to the severity of hypoxia. Unravelling of the complex functions of HIF-1α may be important when designing neuroprotective therapies for hypoxic–ischemic brain injury.
Keyword Hypoxia-inducible factor
Hypoxia
Ischemia
Brain injury
Neonate
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Critical review of research, literature review, critical commentary
Collections: UQ Centre for Clinical Research Publications
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