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

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