Identification of Potential Stroke Targets by Lentiviral Vector Mediated Overexpression of HIF-1α and HIF-2α in a Primary Neuronal Model of Hypoxia

Ralph, G; Parham, Stephen; Lee, S R; Beard, G L; Craigon, Marie; Ward, Nicole L.; White, Jonathan; Barber, Robert D.; Rayner, W; Kingsman, Susan M.; Mundy, Christopher R.; Mazarakis, Nicholas D.; Krige, David

doi:10.1097/01.wcb.0000110532.48786.46

Cited by 44 publications

(37 citation statements)

References 91 publications

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“…However, it remained to be determined whether activation of HIF-1␣ or HIF-2␣ was responsible in these studies. Recent studies that used a lentiviral vector system to express HIF-1␣ and HIF-2␣ identified novel genes that were activated by a combination of HIF-2␣ overexpression and hypoxic insult, suggesting a critical role for HIF-2␣ in mediating protective responses against ischemic injury (30). To our knowledge, this is the first report to clarify direct evidence of a protective role of HIF-2␣ against an exogenous insult in vivo.…”

Section: Discussionmentioning

confidence: 69%

Protective Role of Hypoxia-Inducible Factor-2α against Ischemic Damage and Oxidative Stress in the Kidney

Kojima¹,

Tanaka²,

Inagi³

et al. 2007

Journal of the American Society of Nephrology

117

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Central to cellular responses to hypoxic environment is the hypoxia-inducible factor (HIF) transcriptional control system. A role for HIF-2␣ was investigated in a model of renal ischemia-reperfusion injury (IRI) associated with oxidative stress using HIF-2␣ knockdown mice. In these mice, HIF-2␣ expression was approximately one half that of wild-type mice, whereas HIF-1␣ expression was equivalent. HIF-2␣ knockdown mice were more susceptible to renal IRI, as indicated by elevated blood urea nitrogen levels and semiquantitative histologic analysis. Immunostaining with markers of oxidative stress showed enhanced oxidative stress in the kidney of HIF-2␣ knockdown mice, which was associated with peritubular capillary loss. C ellular responses to oxygen play an important role in many aspects of physiologic homeostasis. Central to these responses is the hypoxia-inducible factor (HIF) transcriptional control system (1-3). HIF is a heterodimeric transcription factor that is composed of ␣ and ␤ subunits. Whereas HIF-1␣ is known as a key regulator in a wide range of cellular adaptation responses to hypoxia, relatively little is known about biologic significance of its isoform, HIF-2␣.Although ischemic renal injury plays a major role in acute renal failure, tubulointerstitial hypoxia has also been implicated in the pathogenesis and progression of chronic renal disease regardless of the underlying disease (4 -7). In the kidney, HIF-1␣ is induced mainly in tubular and glomerular epithelial cells in response to hypoxia, whereas HIF-2␣ is localized in glomerular cells, peritubular endothelial cells, and fibroblasts (8 -10). Because mice with complete deficiency of HIF-2␣ are embryonic or perinatal lethal (11-13), analysis of a biologic function of HIF-2␣ after birth has been hampered. To study a postnatal biologic role of HIF-2␣, we previously established HIF-2␣ knockdown (kd) mice. These mice show normal development, whereas expression of HIF-2␣ mRNA in the kidney was reduced to 50% without any changes of HIF-1␣ mRNA expression (14). In this study, we induced the well-established ischemia-reperfusion injury (IRI) model of the kidney in HIF-2␣ kd mice to clarify a pathophysiologic role of HIF-2␣ in adult mice. Materials and Methods AnimalsHIF-2␣ kd mice were generated as described previously. This mice were viable and fertile, and also our screening did not reveal any pathologic abnormalities as we previously described (14). These mice were back-crossed with C57BL/6J mice for nine generations. Male C57BL/6J wild-type (WT) and homozygous HIF-2␣ kd mice at the age of 6 to 8 wk were used. To rescue HIF-2␣ specifically in the endothelium, we used for intercrossing Tie1-Cre transgenic (Tie1-Cre) mice (15) whose genetic background was C57BL/6J. Mice were housed in a specific pathogen-free facility and were confirmed to be negative for common murine viral pathogens by routine sera analyses. All experiments were conducted in accordance with the Guide for Animal Experimentation at the University of Tokyo.

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Section: Discussionmentioning

confidence: 69%

Protective Role of Hypoxia-Inducible Factor-2α against Ischemic Damage and Oxidative Stress in the Kidney

Kojima¹,

Tanaka²,

Inagi³

et al. 2007

Journal of the American Society of Nephrology

117

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“…The advantage of this strategy as compared to prior "antioxidants" is the ability of a single drug to selectively target a single molecule (i.e. PHD) that will activate more than seventy genes providing adaptation to ischemia and oxidative stress (35,81,82) (Figure 2). …”

Section: The Hypoxia-inducible-factors (Hif)mentioning

confidence: 99%

Prolyl 4-hydroxylase activity-responsive transcription factors: From hydroxylation to gene expression and neuroprotection

Siddiq

Aminova²,

Ratan³

2008

Front Biosci

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Most homeostatic processes including gene transcription occur as a result of deviations in physiological tone that threatens the survival of the organism. A prototypical homeostatic stress response includes changes in gene expression following alterations in oxygen, iron or 2-oxoglutarate levels. Each of these cofactors plays an important role in cellular metabolism. Accordingly, a family of enzymes known as the Prolyl 4-hydroxylase (PHD) enzymes are a group of dioxygenases that have evolved to sense changes in 2-oxoglutarate, oxygen and iron via changes in enzyme activity. Indeed, PHDs are a part of an established oxygen sensor system that regulates transcriptional regulation of hypoxia/stress-regulated genes and thus are an important component of events leading to cellular rescue from oxygen, iron or 2-oxoglutarate deprivations. The ability of PHD activity to regulate homeostatic responses to oxygen, iron or 2-oxoglutarate metabolism has led to the development of small molecule inhibitors of the PHDs as a strategy for activating or augmenting cellular stress responses. These small molecules are proving effective in preclinical models of stroke and Parkinson's disease. However the precise protective pathways engaged by PHD inhibition are only beginning to be defined. In the current review, we summarize the role of iron, 2-oxoglutarate and oxygen in the PHD catalyzed hydroxylation reaction and provide a brief discussion of some of the transcription factors that play an effective role in neuroprotection against oxidative stress as a result of changes in PHD activity.

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“…To this end, a HIF-related database was constructed from reviews 32,33 and two original studies. 34,35 (D) The gene had to have a role in vasculogenesis, angiogenesis or vascular function. A role in the brain (including the blood-brain barrier), in large extracranial vessels or endothelial cells was ascertained by screening PubMed abstracts.…”

Section: Selection Of Susceptibility Genes From Association Studiesmentioning

confidence: 99%

An environmental analysis of genes associated with schizophrenia: hypoxia and vascular factors as interacting elements in the neurodevelopmental model

et al. 2012

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Investigating and understanding gene-environment interaction (G Â E) in a neurodevelopmentally and biologically plausible manner is a major challenge for schizophrenia research. Hypoxia during neurodevelopment is one of several environmental factors related to the risk of schizophrenia, and links between schizophrenia candidate genes and hypoxia regulation or vascular expression have been proposed. Given the availability of a wealth of complex genetic information on schizophrenia in the literature without knowledge on the connections to environmental factors, we now systematically collected genes from candidate studies (using SzGene), genome-wide association studies (GWAS) and copy number variation (CNV) analyses, and then applied four criteria to test for a (theoretical) link to ischemia-hypoxia and/or vascular factors. In all, 55% of the schizophrenia candidate genes (n = 42 genes) met the criteria for a link to ischemia-hypoxia and/or vascular factors. Genes associated with schizophrenia showed a significant, threefold enrichment among genes that were derived from microarray studies of the ischemia-hypoxia response (IHR) in the brain. Thus, the finding of a considerable match between genes associated with the risk of schizophrenia and IHR and/or vascular factors is reproducible. An additional survey of genes identified by GWAS and CNV analyses suggested novel genes that match the criteria. Findings for interactions between specific variants of genes proposed to be IHR and/or vascular factors with obstetric complications in patients with schizophrenia have been reported in the literature. Therefore, the extended gene set defined here may form a reasonable and evidence-based starting point for hypothesis-based testing of G Â E interactions in clinical genetic and translational neuroscience studies.

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Identification of Potential Stroke Targets by Lentiviral Vector Mediated Overexpression of HIF-1α and HIF-2α in a Primary Neuronal Model of Hypoxia

Cited by 44 publications

References 91 publications

Protective Role of Hypoxia-Inducible Factor-2α against Ischemic Damage and Oxidative Stress in the Kidney

Protective Role of Hypoxia-Inducible Factor-2α against Ischemic Damage and Oxidative Stress in the Kidney

Prolyl 4-hydroxylase activity-responsive transcription factors: From hydroxylation to gene expression and neuroprotection

An environmental analysis of genes associated with schizophrenia: hypoxia and vascular factors as interacting elements in the neurodevelopmental model

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