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

被引:171
作者
Fan, Xiyong [1 ,2 ,3 ]
Heijnen, Cobi J. [2 ]
van der Kooij, Michael A. [1 ,2 ]
Groenendaal, Floris [1 ]
van Bel, Frank [1 ]
机构
[1] Wilhelmina Childrens Hosp, Univ Med Ctr Utrecht, Dept Neonatol, NL-3584 EA Utrecht, Netherlands
[2] Wilhelmina Childrens Hosp, Univ Med Ctr Utrecht, Lab Psychoneuroimmunol, NL-3584 EA Utrecht, Netherlands
[3] Peking Univ, Hosp 1, Dept Paediat, Beijing 100034, Peoples R China
关键词
Hypoxia-inducible factor; Hypoxia; Ischemia; Brain injury; Neonate; ENDOTHELIAL GROWTH-FACTOR; FOCAL CEREBRAL-ISCHEMIA; CENTRAL-NERVOUS-SYSTEM; APOPTOTIC GENE BNIP3; FACTOR-I HIF-1; CELL-DEATH; BARRIER PERMEABILITY; TARGET GENES; RAT-BRAIN; TRANSDUCTION PATHWAYS;
D O I
10.1016/j.brainresrev.2009.09.006
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
During neonatal hypoxic-ischemic brain injury, activation of transcription of a series of genesis induced to stimulate erythropoiesis, anti-apoptosis, apoptosis, necrosis and angiogenesis A key factor mediating these gene transcriptions is hypoxia-inducible factor-1 alpha (HIF-1 alpha) During hypoxia, HIF-1 alpha protein is stabilized and heterodimenzes with HIF-1 beta to form HIF-1, subsequently regulating the expression of target genes HIF-1 alpha participates in early brain development and proliferation of neuronal precursor cells Under pathological conditions, HIF-1 alpha is known to play an important role in neonatal hypoxic-ischemic brain Injury on the one hand, HIF-1 alpha has neuroprotective effects whereas it can also have neurotoxic effects HIF-1 alpha regulates the transcription of erythropoietin (EPO), which induces several pathways associated with neuroprotection. HIF-1 alpha also promotes the expression of vascular endothelial cell growth factor (VEGF), which is related to neovascularization in hypoxic-ischemic brain areas. In addition, HIF-1 alpha has an anti-apoptotic effect by increasing the expression of anti-apoptotic factors such as EPO during mild hypoxia The neurotoxic effects of HIF-1 alpha are represented by its participation in the apoptotic process by increasing the stability of the tumor suppressor protein p53 during severe hypoxia Moreover, HIF-1 alpha plays a role in cell necrosis, by interacting with calcium and calpain. HIF-1 alpha can also exacerbate brain edema via increasing the permeability of the blood-brain barrier (BBB) Given these properties, HIF-1 alpha 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-1 alpha may be important when designing neuroprotective therapies for hypoxic-ischemic brain injury. Crown Copyright (C) 2009 Published by Elsevier B V. All rights reserved
引用
收藏
页码:99 / 108
页数:10
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