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

doi:10.1016/j.brainresrev.2009.09.006

Brain Research Reviews

Volume 62, Issue 1, 11 December 2009, Pages 99-108

https://doi.org/10.1016/j.brainresrev.2009.09.006 Get rights and content

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.

Introduction

Neonatal brain injury may result from a variety of conditions, including hypoxia–ischemia, intrauterine infection, and perinatal cerebral hemorrhage. The most common cause of neonatal brain damage is hypoxia–ischemia (HI) (Bracci et al., 2006). HI can disturb brain development and can lead to a variety of serious neurological disorders such as motor and learning disabilities, cerebral palsy, epilepsy and seizures. Although advances in obstetric and neonatal care have reduced substantially neonatal morbidity and mortality, subjects suffering from neonatal HI still experience life long cognitive, sensory and motor disabilities (Northington et al., 2001). Many studies have been performed investigating the mechanisms of hypoxic–ischemic brain damage in the past years, such as free radical formation (Kumar et al., 2008), excitotoxicity (Papazisis et al., 2008) and inflammation (Pleasure et al., 2006, Nijboer et al., 2009). Hypoxia-inducible factor-1α (HIF-1α), which was first discovered in human hepatoma cells as a key factor mediating target gene transcriptions in 1988 (Goldberg et al., 1988) has been intensively investigated for its role in the modulation of hypoxic–ischemic brain injury since 1995(van den Tweel et al., 2006, Chen et al., 2009).

In the present article, we first review the current state of knowledge about the role and regulation of HIF-1α expression in brain development and neonatal hypoxic–ischemic brain injury, and then discuss the possible focus for future research in order to design suitable targets for neonatal brain injury therapy.

Section snippets

The structure and paralogs of HIF-1α

HIF-1α is a member of the Hypoxia Inducible Factor (HIF) family. HIF-1α was discovered in 1988 as the 3′ enhancer of the erythropoietin (EPO) gene (Goldberg et al., 1988). The structure of HIF-1α contains two transactivation domains: N-terminal domain (N-TAD) and C-terminal domain (C-TAD). The C-TAD in particular has been shown to regulate the activity of gene transcription (Lando et al., 2002). HIF-1α also contains an oxygen-dependent degradation domain (ODDD) that mediates oxygen-regulated

HIF- 1α degradation and blockade of target genes transcription in normoxia

During normoxia, HIF-1α is bound to the chaperone molecule Hsp90. In the presence of oxygen and 2-oxoglutarate, HIF-1α is hydroxylated by prolyl hydroxylases (PHD). In addition, HIF-1α is acetylated by an acetyltransferase named arrest-defective-1(ARD1). The hydroxylated, acetylated HIF-1α protein is easily recognized and bound by the von Hippel–Lindau protein (pVHL). The binding of pVHL leads to ubiquitination of HIF-1α. The ubiquitinated pVHL/HIF-1α complex targets the HIF-1α protein to the

HIF-1α stabilization in hypoxia

Hypoxia leads to an almost immediate shut down of general protein translation to decrease energy consumption during hypoxic energy starvation (Liu et al., 2006). Simon (2006) reported that PHD activity in the murine embryonic cells was inhibited when the concentration of O₂ was lower than 5%,. In addition to enzymatic inhibition of the PHD, hypoxia causes perturbations in the mitochondrial electron-transport chain, increasing the levels of cytoplasmic reactive-oxygen species (ROS). ROS can

HIF-1α and brain development

The role of HIF-1α in brain development has been investigated for several years. In normal mouse embryos, HIF-1α expression increases between embryonic days 8.5 and 9.5 (Iyer et al., 1998). In neonatal conditional knockout mice after hypoxia (6% O₂ of 3 h), neuron-specific HIF-1α-deficiency led to hydrocephalus accompanied by a reduction in neuronal cells and an impairment of spatial memory at the age of 10 weeks (Tomita et al., 2003). Endogenous hypoxia-inducible mechanisms are crucially

HIF-1α and erythropoiesis, role of erythropoietin

In response to hypoxia, the capacity of red blood cells to transport oxygen is up-regulated by the expression of genes involved in erythropoiesis. Hypoxia increases the expression of EPO, which is required for the formation of red blood cells. EPO has been originally recognized as a humoral mediator involved in the maturation and proliferation of erythroid progenitor cells (van der Kooij et al., 2008). Recent studies have shown that EPO mRNA and the actual EPO protein are found in the brain of

HIF-1α and apoptosis

Neuronal cells undergo apoptosis during and after neonatal HI. HIF-1α is involved in hypoxia-induced apoptosis (Greijer and van der Wall, 2004). There are two possible pathways. First, HIF-1α increases the stability of the tumor suppressor protein p53, which induces cell apoptosis (Chen et al., 2003). Using herpes amplicon-mediated gene transfer in cortical neuronal cultures, expressing a dominant-negative form of HIF-1α (HIFdn) capable of disrupting hypoxia-dependent transcription, reduced

HIF-1α and necrosis

Neuronal cell death after HI occurs via two pathways. One is apoptosis, as we mentioned above, the other is necrosis, an earlier and rapid pathway of neuronal cell death (Hossain, 2008). During studies with a P7 rat HI model, necrotic neuronal cell death predominates in the ischemic core whereas apoptotic neuronal cells distribute mainly in areas with milder ischemic injury (Nakajima et al., 2000).

Neuronal cells are oxygen-sensing cells, which means that the cells respond to hypoxia with an

HIF-1α and angiogenesis, role of vascular endothelial cell growth factor

Angiogenesis is a complex process that involves multiple gene products expressed by different cell types. A large number of molecules serve as positive regulators of angiogenesis (vascular endothelial cell growth factor VEGF, fibroblast growth factors FGFa and FGFb, transforming growth factors TGFα and TGFβ, hepatocyte growth factor HGF, tumor necrosis factor TNFα, angiogenin, interleukin-8, and angiopoietins) and have been shown to increase by hypoxic challenge (Karamysheva, 2008). However,

Other properties of HIF-1

Recent in vitro work suggests that selective loss of HIF-1α function in astrocytes provides neuroprotection after hypoxia, whereas loss of neuronal HIF-1α increases neuronal susceptibility to hypoxia-induced damage (Vangeison et al., 2008). The latter suggests that the HI-induced effects of HIF-1α might be cell type specific. Astrocytes can contact the brain vasculature with their end feet processes and this interaction is thought to induce endothelial tight junction formation and to decrease

HIF-1α and hypoxic/ischemic preconditioning

As we have mentioned before, HI is an important cause of neonatal brain injury. However, a sublethal hypoxic/ischemic exposure can improve tolerance of tissue or of cells to a subsequent lethal hypoxic/ischemic insult. This phenomenon is called hypoxic/ischemic preconditioning (H/IPC), actually occurring during perinatal hypoxia (Wang et al., 2008, Murry et al., 1986).

Studies have indicated that HIF-1α is a key factor involved in H/IPC. In a P7 rat model, the expression of HIF-1α was

Regulatory factors of HIF-1α expression in neonatal hypoxia–ischemia

Many factors can regulate the expression and stabilization of HIF-1α. PHD, an oxygen related enzyme, may suppress HIF-1α function. As we mentioned before, PHD can hydroxylate HIF-1α which will lead to the subsequent degradation of HIF-1α. After P6 rats were exposed to preconditioning with hypoxia (3 h, 8% O₂), HIF-1α significantly increased in brain tissue immediately while PHD activities were inhibited simultaneously (Jones et al., 2006). PHD can also be inhibited by other factors without

Conclusions and recommendations

HIF-1α plays an important role in brain development and hypoxic–ischemic brain injury, and the molecule exhibits both neuroprotective as well as neurotoxic properties. A myriad of factors are involved in the regulation of HIF-1α expression. Despite the recent rapid advance in the understanding of molecular mechanisms in response to HI in neonatal brain injury, many questions about HIF-1α remain to be answered. The regulation of HIF-1α expression and the distinct roles of HIF-1α during neuronal

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

Abstract

Introduction

Section snippets

The structure and paralogs of HIF-1α

HIF- 1α degradation and blockade of target genes transcription in normoxia

HIF-1α stabilization in hypoxia

HIF-1α and brain development

HIF-1α and erythropoiesis, role of erythropoietin

HIF-1α and apoptosis

HIF-1α and necrosis

HIF-1α and angiogenesis, role of vascular endothelial cell growth factor

Other properties of HIF-1

HIF-1α and hypoxic/ischemic preconditioning

Regulatory factors of HIF-1α expression in neonatal hypoxia–ischemia

Conclusions and recommendations

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Cell

Neurobiol. Dis.

J. Biol. Chem.

Neurobiol. Dis.

Exp. Neurol.

Am. J. Pathol.

Int. J. Dev. Neurosci.

Neurosci. Lett.

Neuroscience

Brain Res.

Mol. Cell

Blood

Exp. Neurol.

Am. J. Pathol.

Free Radic. Biol. Med.

Neurobiol. Dis.

Exp. Neurol.

Pharmacol. Res.

Biochem. Pharmacol.

Brain Behav. Immun.

Neuroscience

Brain Res.

J. Biol. Chem.

Cell Calcium

NeuroRx

J. Biol. Chem.

Clin. Neurosci.

Brain Res. Rev.

J. Biol. Chem.

Semin. Oncol.

Blood

Constitutive expression of hypoxia-inducible factor-1alpha renders pancreatic cancer cells resistant to apoptosis induced by hypoxia and nutrient deprivation

Cancer Res.

Antioxidants, HIF prolyl hydroxylase inhibitors or short interfering RNAs to BNIP3 or PUMA, can prevent prodeath effects of the transcriptional activator, HIF-1alpha, in a mouse hippocampal neuronal line

Antioxid. Redox Signal.

IL-1beta regulates blood–brain barrier permeability via reactivation of the hypoxia-angiogenesis program

J. Immunol.

Neuron-specific inactivation of the hypoxia inducible factor 1 alpha increases brain injury in a mouse model of transient focal cerebral ischemia

J. Neurosci.

Induction of hypoxia-inducible factor-1 (HIF-1) and its target genes following focal ischaemia in rat brain

Eur. J. Neurosci.

Role of hypoxia-inducible factor-1 in hypoxia-induced ischemic tolerance in neonatal rat brain

Ann. Neurol.

Normobaric hypoxia induces tolerance to focal permanent cerebral ischemia in association with an increased expression of hypoxia-inducible factor-1 and its target genes, erythropoietin and VEGF, in the adult mouse brain

J. Cereb. Blood Flow Metab.

The timing of neonatal brain damage

Biol. Neonate

Oxygen treatment after experimental hypoxia–ischemia in neonatal rats alters the expression of HIF-1alpha and its downstream target genes

J. Appl. Physiol.

The E1B 19K/Bcl-2-binding protein Nip3 is a dimeric mitochondrial protein that activates apoptosis

J. Exp. Med.

Up-regulation of vascular endothelial growth factor expression in a rat glioma is conferred by two distinct hypoxia-driven mechanisms

Cancer Res.

Neuroprotective effects of vascular endothelial growth factor following hypoxic ischemic brain injury in neonatal rats

Pediatr. Res.

Activation of vascular endothelial growth factor gene transcription by hypoxia inducible factor 1

Mol. Cell Biol.

PHDs overactivation during chronic hypoxia “desensitizes” HIFalpha and protects cells from necrosis

Proc. Natl. Acad. Sci. U. S. A.

Regulation of the erythropoietin gene: evidence that the oxygen sensor is a heme protein

Science

The role of hypoxia inducible factor 1 (HIF-1) in hypoxia induced apoptosis

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