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

Fan, Xiyong; Heijnen, Cobi J.; Kooij, Michael A. van der; Groenendaal, Floris; Bel, Floris van

doi:10.1016/j.brainresrev.2009.09.006

Cited by 173 publications

(161 citation statements)

References 96 publications

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“…On the other hand, p53 expression was not increased in the L group. The gene expression of p53 is increased in severe hypoxia (Li et al 1994;An et al 1998;Hammond et al 2002;Fan et al 2009). In addition, severe hypoxia induces IUGR and abortion (Rueda-Clausen et al 2009).…”

Section: Discussionmentioning

confidence: 99%

Maternal Undernutrition Induces the Expression of Hypoxia-Related Genes in the Fetal Brain

Ito

Funamoto

Sato

et al. 2012

Tohoku J. Exp. Med.

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Maternal undernutrition during pregnancy is a risk factor for cerebrovascular and cardiovascular diseases in adulthood. Hypoxia-inducible factor 1 alpha (HIF1α) plays an essential role in cellular hypoxic responses, and its increased expression is associated with cerebrovascular and cardiovascular diseases. However, it is not known whether maternal undernutrition influences HIF1α expression in the fetal brain. We therefore analyzed the expression levels of HIF1α and its downstream genes in the fetal brain (day 17.5 of gestation, 1-2 days before birth). Maternal undernutrition did not noticeably affect the fetal body and brain weights. Both HIF1α mRNA and protein levels were increased in the brain under maternal undernutrition, despite the absence of hypoxia, as judged by the staining profile with hypoxyprobe-1 that identifies hypoxic cells. Importantly, maternal undernutrition caused the accumulation of HIF1α protein in oligodendrocyte precursor cells at the subventricular zone, a site of neurogenesis in the fetal brain. Maternal undernutrition also increased the mRNA level of mammalian target of rapamycin (mTOR), which could increase the level of HIF1α protein under normoxia. Furthermore, microarray analysis revealed that expression levels of mRNAs for 10 HIF1α downstream targets, including enolase 1 and hexokinase 1, were increased in the fetal brain under maternal undernutrition. Thus, the biochemical consequence of maternal undernutrition is similar to that of mild hypoxia. In conclusion, maternal undernutrition induces the expression of HIF1α in oligodendrocyte precursor cells at the subventricular zone, and it also induces the expression of hypoxia-related genes in the fetal brain probably via activation of the mTOR pathway.Keywords: fetal brain; hypoxia-inducible factor 1 alpha; hypoxic responses; mammalian target of rapamycin; maternal undernutrition Tohoku J. Exp. Med., 2012, 226 (1), 37-44.

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Section: Discussionmentioning

confidence: 99%

Maternal Undernutrition Induces the Expression of Hypoxia-Related Genes in the Fetal Brain

Ito

Funamoto

Sato

et al. 2012

Tohoku J. Exp. Med.

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“…Interestingly, NMNAT1 and HIF α peripheral blood mRNA levels are also increased in people living at high altitudes suggesting that the expression of HIF α and NMNATs is also adaptive to low oxygen conditions in humans 33, 34. Moreover, HIF α is a transcription factor importantly involved in the regulation of neuronal survival of injured neurons following neonatal H‐I and it is also actively upregulated in response to repeated neonatal cerebral hypoxia 35. Therefore, increases in the endogenous expression of NMNAT3 in response to neonatal cerebral hypoxia and ischemia may represent an internal mechanism by which the immature neuron attempts to protect itself from the degenerative effects brought on by excessive metabolic stress.…”

Section: Discussionmentioning

confidence: 99%

NMNAT3 is protective against the effects of neonatal cerebral hypoxia‐ischemia

Galindo

Greenberg

Araki

et al. 2017

Ann Clin Transl Neurol

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ObjectiveTo determine whether the NAD+ biosynthetic protein, nicotinamide mononucleotide adenylyltransferase‐3 (NMNAT3), is a neuroprotective inducible enzyme capable of decreasing cerebral injury after neonatal hypoxia‐ischemia (H‐I) and reducing glutamate receptor‐mediated excitotoxic neurodegeneration of immature neurons.MethodsUsing NMNAT3‐overexpressing mice we investigated whether increases in brain NMNAT3 reduced cerebral tissue loss following H‐I. We then employed biochemical methods from injured neonatal brains to examine the inducibility of NMNAT3 and the mechanism of NMNAT3‐dependent neuroprotection. Using AAV8‐mediated vectors for in vitro neuronal NMNAT3 knockdown, we then examine the endogenous role of this protein on immature neuronal survival prior and following NMDA receptor‐mediated excitotoxicity.ResultsNMNAT3 mRNA and protein levels increased after neonatal H‐I. In addition, NMNAT3 overexpression decreased cortical and hippocampal tissue loss 7 days following injury. We further show that the NMNAT3 neuroprotective mechanism involves a decrease in calpastatin degradation, and a decrease in caspase‐3 activity and calpain‐mediated cleavage. Conversely, NMNAT3 knockdown of cortical and hippocampal neurons in vitro caused neuronal degeneration and increased excitotoxic cell death. The neurodegenerative effects of NMNAT3 knockdown were counteracted by exogenous upregulation of NMNAT3.ConclusionsOur observations provide new insights into the neuroprotective mechanisms of NMNATs in the injured developing brain, adding NMNAT3 as an important neuroprotective enzyme in neonatal H‐I via inhibition of apoptotic and necrotic neurodegeneration. Interestingly, we find that endogenous NMNAT3 is an inducible protein important for maintaining the survival of immature neurons. Future studies aimed at uncovering the mechanisms of NMNAT3 upregulation and neuroprotection may offer new therapies against the effects of hypoxic‐ischemic encephalopathy.

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“…HIF-1 is a nuclear protein that activates gene transcription, including that of EPO, VEGF, iNOS and heme oxygenase-1, in response to cellular hypoxia. [4,9] HIF-1 is a heterodimer composed of HIF-1α and HIF-1β subunits. Both subunits are induced by hypoxia and rapidly decay upon return to normoxia.…”

Section: Discussionmentioning

confidence: 99%

“…[9] VEGF is a very important target gene of HIF-1α, and a major regulator of angiogenesis. [4] After hypoxiaischemia, the over-expression of HIF-1α induces an increase in VEGF expression. [4,10] VEGF can promote angiogenesis and microcirculation reconstruction, and thus increase the blood and oxygen supply to ischemic tissues and contribute to the recovery from brain injury caused by ischemia and hypoxia.…”

Section: Discussionmentioning

confidence: 99%

“…[4] After hypoxiaischemia, the over-expression of HIF-1α induces an increase in VEGF expression. [4,10] VEGF can promote angiogenesis and microcirculation reconstruction, and thus increase the blood and oxygen supply to ischemic tissues and contribute to the recovery from brain injury caused by ischemia and hypoxia. [4] Over-expression of VEGF can also exert protective effects on brain ischemia-reperfusion injury by protecting endothelial cells, reducing brain edema, and scavenging oxygen free radicals.…”

Section: Discussionmentioning

confidence: 99%

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Effect of β-sodium aescinate on hypoxia-inducible factor-1α expression in rat brain cortex after cardiopulmonary resuscitation

Kang¹,

Gong²,

Ren³

et al. 2013

World Journal of Emergency Medicine

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

Cited by 173 publications

References 96 publications

Maternal Undernutrition Induces the Expression of Hypoxia-Related Genes in the Fetal Brain

Maternal Undernutrition Induces the Expression of Hypoxia-Related Genes in the Fetal Brain

NMNAT3 is protective against the effects of neonatal cerebral hypoxia‐ischemia

Effect of β-sodium aescinate on hypoxia-inducible factor-1α expression in rat brain cortex after cardiopulmonary resuscitation

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