Contribution of HIF-1α or HIF-2α to erythropoietin expression: in vivo evidence based on chromatin immunoprecipitation

Yeo, Eui‐Ju; Cho, Young Suk; Kim, Myung Suk; Park, Jong-Wan

doi:10.1007/s00277-007-0359-6

Cited by 53 publications

(47 citation statements)

References 26 publications

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“…These data are consistent with previous reports showing that endogenous brain Epo production by astrocytes is up-regulated by hypoxia (29). Interestingly, rEpo treatment decreased this up-regulation, suggesting a possible feedback mechanism.…”

Section: Discussionsupporting

confidence: 83%

Microarray Analysis of High-Dose Recombinant Erythropoietin Treatment of Unilateral Brain Injury in Neonatal Mouse Hippocampus

et al. 2009

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Recombinant human erythropoietin (rEpo) is neuroprotective in neonatal models of brain injury. Proposed mechanisms of neuroprotection include activation of gene pathways that decrease oxidative injury, inflammation, and apoptosis, while increasing vasculogenesis and neurogenesis. To determine the effects of rEpo on gene expression in 10-d-old BALB-c mice with unilateral brain injury, we compared microarrays from the hippocampi of braininjured pups treated with saline or rEpo to similarly treated sham animals. Total RNA was extracted 24 h after brain injury and analyzed using Affymetrix GeneChip Mouse Exon 1.0 ST Arrays. We identified sex-specific differences in hippocampal gene expression after brain injury and after high-dose rEpo treatment using single-gene and gene set analysis. Although high-dose rEpo had minimal effects on hippocampal gene expression in shams, at 24-h post brain injury, high-dose rEpo treatment significantly decreased the proinflammatory and antiapoptotic response noted in saline-

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Section: Discussionsupporting

confidence: 83%

Microarray Analysis of High-Dose Recombinant Erythropoietin Treatment of Unilateral Brain Injury in Neonatal Mouse Hippocampus

et al. 2009

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“…33 Furthermore, factor-inhibiting HIF-1 was reported to act less active on HIF-2␣ than on HIF-1␣, conferring increased HIF-2 transcriptional activity under normoxia. 34,35 Because Epo expression in the brain is controlled by HIF-2 rather than HIF-1, 36,37 this, together with our finding that HIF-2␣ protein is stabilized in healthy nPhd2 ⌬/⌬ mice, strongly indicates that Epo upregulation in Phd2-deficient brain in normoxia is at least partially mediated in a HIF-2-dependent manner.…”

Section: Involvement Of the Hif Pathwaysupporting

confidence: 48%

Neuron-Specific Prolyl-4-Hydroxylase Domain 2 Knockout Reduces Brain Injury After Transient Cerebral Ischemia

Kunze

Zhou

Veltkamp

et al. 2012

Stroke

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Background and Purpose-Numerous factors involved in the adaptive response to hypoxia, including erythropoietin and vascular endothelial growth factor are transcriptionally regulated by hypoxia-inducible factors (HIFs). During normoxia, prolyl-4-hydroxylase domain (PHD) proteins hydroxylate HIF-␣ subunits, resulting in their degradation. We investigated the effect of neuronal deletion of PHD2, the most abundant isoform in brain, for stroke outcome. Methods-We generated neuron-specific Phd2 knockout mice and subjected animals to systemic hypoxia or transient middle cerebral artery occlusion. Infarct volume and cell death were determined by histology. HIF-1␣, HIF-2␣, and HIF target genes were analyzed by immunoblotting and real-time polymerase chain reaction, respectively. Results-Neuron-specific ablation of Phd2 significantly increased protein stability of HIF-1␣ and HIF-2␣ in the forebrain and enhanced expression of the neuroprotective HIF target genes erythropoietin and vascular endothelial growth factor as well as glucose transporter and glycolysis-related enzymes under hypoxic and ischemic conditions. Mice with Phd2-deficient neurons subjected to transient cerebral ischemia exhibited a strong reduction in infarct size, and cell death of hippocampal CA1 neurons located in the peri-infarct region was dramatically reduced in these mice. Vessel density in forebrain subregions, except for caudate-putamen, was not altered in Phd2-deficient animals. Conclusions-Our findings denote that the endogenous adaptive response on hypoxic-ischemic insults in the brain is at least partly dependent on the activity of HIFs and identify PHD2 as the key regulator for the protective hypoxia response. The results suggest that specific inhibition of PHD2 may provide a useful therapeutic strategy to protect brain tissue from ischemic injury. (Stroke. 2012;43:2748-2756.)

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“…48 Moreover, abrogation of HIF-2a but not HIF-1a Figure 7. Continued macrophages within non-ischemic contralateral and ischemic ipsilateral hemisphere was determined using immunofluorescence microscopy.…”

Section: Role Of Hif-1 and Hif-2mentioning

confidence: 99%

Neuronal HIF-1α and HIF-2α deficiency improves neuronal survival and sensorimotor function in the early acute phase after ischemic stroke

Barteczek

Ernst

et al. 2016

J Cereb Blood Flow Metab

105

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Hypoxia-inducible factors mediate adaptive responses to ischemia, among others, by induction of anti-and pro-survival genes. Thus, the impact of HIF on neuronal survival upon stroke is controversial. Therefore, neuron-specific knockout mice deficient for Hif1a and Hif2a were exposed to inspiratory hypoxia or ischemia-reperfusion injury. Both Hif1a-and Hif2a-deficient mice showed no altered infarct and edema size, suggesting that both HIF-a subunits might compensate for each other. Accordingly, hypoxic HIF-target gene regulation was marginally affected with exception of anti-survival Bnip3 and pro-survival erythropoietin. In the early acute stage upon stroke, Hif1a/Hif2a double knockout mice exhibited significantly reduced expression of the anti-survival Bnip3, Bnip3L, and Pmaip1. Accordingly, global cell death and edema were significantly reduced upon 24 h but not 72 h reperfusion. Behavioral assessment indicated that Hif1a/ Hif2a-deficient mice initially performed better, but became significantly more impaired after 72 h accompanied by increased apoptosis and reduced angiogenesis. Our findings suggest that in neurons HIF-1 and HIF-2 have redundant functions for cellular survival under ischemic conditions. By contrast, lack of anti-survival factors in Hif1a/Hif2a-deficient mice might protect from early acute neuronal cell death and neurological impairment, indicating a benefit of HIF-pathway inhibition in neurons in the very acute phase after ischemic stroke.

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Contribution of HIF-1α or HIF-2α to erythropoietin expression: in vivo evidence based on chromatin immunoprecipitation

Cited by 53 publications

References 26 publications

Microarray Analysis of High-Dose Recombinant Erythropoietin Treatment of Unilateral Brain Injury in Neonatal Mouse Hippocampus

Microarray Analysis of High-Dose Recombinant Erythropoietin Treatment of Unilateral Brain Injury in Neonatal Mouse Hippocampus

Neuron-Specific Prolyl-4-Hydroxylase Domain 2 Knockout Reduces Brain Injury After Transient Cerebral Ischemia

Neuronal HIF-1α and HIF-2α deficiency improves neuronal survival and sensorimotor function in the early acute phase after ischemic stroke

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