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Hypoxia Inducible Factor-1: Its Potential Role In Cerebral Ischemia

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Abstract

A divergence in the supply and consumption of oxygen in brain tissue initiates complex cycle of biochemical and molecular events resulting in neuronal death. To overcome such adverse situation, the tissue has to adopt some cellular mechanisms such as induction of various transcription factors, such as hypoxia inducible factor (HIF). It is a transcriptional regulator of oxygen homeostasis and key factor to generate the adaptive responses through upregulation of various target genes involved in the erythropoiesis, angiogenesis as well as glucose metabolism and transport. On the other hand, some studies do suggest that HIF also plays a detrimental role in ischemic reperfusion injury by inducing the pro apoptotic molecules, cytokines such as Nix, BNip3, and IL-20 which cause mitochondrial dysfunction leading to cell death. Hence, modulation of HIF-1 activity seems to provide an innovative therapeutic target to reduce the cellular damage, which arises from ischemic injury. Apart from traditional oxygen dependent HIF regulation, the focus has now shifted toward oxygen independent regulation in cell specific manner through reactive oxygen species involving hypoxia-associated factor, and heat shock protein 90, etc. Therefore, future development of such small molecule regulators for HIF-1 stability and signaling may prove useful to therapeutically target for enhancing recovery and repair in I/R injury.

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Abbreviations

17-AAG:

17-Allylaminogeldanamycin

AD:

Alzheimer disease

Ahr:

Aryl hydrocarbon receptor

ARD1:

Arrest defective protein

ARNT:

Aryl hydrocarbon receptor nuclear transporter

CBP:

cAMP-response element-binding protein

Cbz-LLL:

N-carbobenzoxyl-l-leucinyl-l-leucinyl-l-norvalinal

DFO:

Desferoxamine

DHB:

Dihydroxybenzoic acid

DMOG:

Dimethyloxallyl glycine

Epo:

Erythropoietin

ePAS1:

Endothelial PAS domain protein 1

FIH:

Factor-inhibiting hypoxia

GSK:

Glycogen synthase kinase

GLUT:

Glucose transporter

HAF:

Hypoxia-associated factor

HIF-1:

Hypoxia inducible factor-1

HLH:

Helix–loop–helix

HRD:

Hypoxia-responsive domain

HO:

Hemo oxygenase

HRE:

Hypoxia-responsive element

HSP:

Heat shock protein

iNOS:

Inducible nitric oxide synthase

I/R injury:

Ischemia reperfusion injury

LDH:

Lactate dehydrogenase

MCAO:

Middle cerebral artery occlusion

2ME:

2-Methoxyestradiol

MMP:

Matrix metalloproteinase

Ngb:

Neuroglobin

NGF:

Nerve growth factor

ODDD:

Oxygen-dependent degradation domain

PHD:

Prolyl 4-hydroxylase enzyme

pVHL:

Von Hippel–Lindau tumor suppressor protein

PI3K:

Phosphatidylinositol 3-kinase

ROS:

Reactive oxygen species

PTEN:

Phosphatase/tensin homolog deleted on chromosome 10

RACK:

Receptor of activated protein kinase C

SUMO:

Small ubiquitin-like modifiers

SENP:

Sentrin-specific peptidase

VEGF:

Vascular endothelial growth factor

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Acknowledgments

Ms. Neetu Singh and Mr. Vikas Mishra received financial support from CSIR, New Delhi, and Mr.Gaurav Sharma was supported by MOES, New Delhi.

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  1. Division of Pharmacology, CSIR-Central Drug Research Institute, P.O. Box 173, Lucknow, 226001, UP, India

    Neetu Singh, Gaurav Sharma, Vikas Mishra & Ram Raghubir

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  1. Neetu Singh
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Correspondence to Ram Raghubir.

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CDRI Communication Number-8187.

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Singh, N., Sharma, G., Mishra, V. et al. Hypoxia Inducible Factor-1: Its Potential Role In Cerebral Ischemia. Cell Mol Neurobiol 32, 491–507 (2012). https://doi.org/10.1007/s10571-012-9803-9

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