In VivoExpression of mRNAs Encoding Hypoxia-Inducible Factor 1

Wiener, Charles; Booth, Gregory M.; Semenza, Gregg L.

doi:10.1006/bbrc.1996.1199

Cited by 382 publications

(285 citation statements)

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“…In particular, the α subunits of HIF (HIF-1α and HIF-2α) are stabilized and accumulate upon hypoxia (34). In addition, several in vivo studies showed increased levels of HIF-1α mRNA (35,36). We found that EPO induction in EAE is paralleled by an elevation of HIF-1α, but not HIF-2α, mRNA.…”

Section: Discussionmentioning

confidence: 58%

Endogenous Erythropoietin as Part of the Cytokine Network in the Pathogenesis of Experimental Autoimmune Encephalomyelitis

Mengozzi

Cervellini

Bigini

et al. 2008

Mol Med

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Erythropoietin (EPO) is of great interest as a therapy for many of the central nervous system (CNS) diseases and its administration is protective in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Endogenous EPO is induced by hypoxic/ischemic injury, but little is known about its expression in other CNS diseases. We report here that EPO expression in the spinal cord is induced in mouse models of chronic or relapsing-remitting EAE, and is prominently localized to motoneurons. We found a parallel increase of hypoxia-inducible transcription factor (HIF)-1α, but not HIF-2α, at the mRNA level, suggesting a possible role of non-hypoxic factors in EPO induction. EPO mRNA in the spinal cord was co-expressed with interferon (IFN)-γ and tumor necrosis factor (TNF), and these cytokines inhibited EPO production in vitro in both neuronal and glial cells. Given the known inhibitory effect of EPO on neuroinflammation, our study indicates that EPO should be viewed as part of the inflammatory/anti-inflammatory network in MS.

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Section: Discussionmentioning

confidence: 58%

Endogenous Erythropoietin as Part of the Cytokine Network in the Pathogenesis of Experimental Autoimmune Encephalomyelitis

Mengozzi

Cervellini

Bigini

et al. 2008

Mol Med

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“…In addition, given the widespread tropism of AAV (23) and its capability for long-term expression of therapeutic genes, the prevalence of hypoxia as a principal trigger of injury in diverse tissues, the ubiquitous distribution of hypoxia-inducible factor 1␣ (24,25), and the effectiveness of HO-1 in mediating tissue protection from I͞R injury, this approach is generally applicable to a variety of tissues that may undergo I͞R injury, such as the kidneys, lungs, liver, and brain. The selection of HO-1 as a therapeutic target from among many other potential therapeutic genes, such as superoxide dismutase (26), nitric oxide synthase (27,28), and vascular endothelial growth factor (29), was made on the basis of its documented cytoprotective effects (30,31) for the purpose of demonstrating the feasibility and therapeutic potential of this strategy with a validated cardioprotective gene.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia-regulated therapeutic gene as a preemptive treatment strategy against ischemia/reperfusion tissue injury

Pachori

Melo

Hart

et al. 2004

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

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Ischemia and reperfusion represent major mechanisms of tissue injury and organ failure. The timing of administration and the duration of action limit current treatment approaches using pharmacological agents. In this study, we have successfully developed a preemptive strategy for tissue protection using an adenoassociated vector system containing erythropoietin hypoxia response elements for ischemia-regulated expression of the therapeutic gene human heme-oxygenase-1 (hHO-1). We demonstrate that a single administration of this vector several weeks in advance of ischemia͞reperfusion injury to multiple tissues such as heart, liver, and skeletal muscle yields rapid and timely induction of hHO-1 during ischemia that resulted in dramatic reduction in tissue damage. In addition, overexpression of therapeutic transgene prevented long-term pathological tissue remodeling and normalized tissue function. Application of this regulatable system using an endogenous physiological stimulus for expression of a therapeutic gene may be a feasible strategy for protecting tissues at risk of ischemia͞reperfusion injury.

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“…The subterranean mole rat (Spalax) thus provides a unique natural model, because it has evolved adaptive strategies to cope with extreme underground conditions of hypoxic stress (20). The high tolerance of Spalax to hypoxia seems related to a wide array of respiratory and cardiovascular adaptations, as reflected in structural and functional properties of several hypoxia-related genes including EPO (21), EPO-R (22), VEGF (23,24), HIF-1 (24,25), and p53 (26,27). The sequence of Spalax EPO-R (sEPO-R) exhibits unique features compared with EPO-R of other mammals (22).…”

Section: Erythropoietic Functions Of Erythropoietin (Epo) Are Mediatementioning

confidence: 99%

An extracellular region of the erythropoietin receptor of the subterranean blind mole rat Spalax enhances receptor maturation

Ravid¹,

Shams²,

Califa³

et al. 2007

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

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Erythropoietic functions of erythropoietin (EPO) are mediated by its receptor (EPO-R), which is present on the cell surface of erythroid progenitors and induced by hypoxia. We focused on EPO-R from Spalax galili (sEPO-R), one of the four Israeli species of the subterranean blind mole rat, Spalax ehrenbergi superspecies, as a special natural animal model of high tolerance to hypoxia. Led by the intriguing observation that most of the mouse EPO-R (mEPO-R) is retained in the endoplasmic reticulum (ER), we hypothesized that sEPO-R is expressed at higher levels on the cell surface, thus maximizing the response to elevated EPO, which has been reported in this species. Indeed, we found increased cell-surface levels of sEPO-R as compared with mEPO-R by using flow cytometry analysis of BOSC cells transiently expressing HA-tagged EPO-Rs (full length or truncated). We then postulated that unique extracellular sEPO-R sequence features contribute to its processing and cell-surface expression. To map these domains of the sEPO-R that augment receptor maturation, we generated EPO-R derivatives in which parts of the extracellular region of mEPO-R were replaced with the corresponding fragments of sEPO-R. We found that an extracellular portion of sEPO-R, harboring the N-glycosylation site, conferred enhanced maturation and increased transport to the cell surface of the respective chimeric receptor.Taken together, we demonstrate higher surface expression of sEPO-R, attributed at least in part to increased ER exit, mediated by an extracellular region of this receptor. We speculate that these sEPO-R sequence features play a role in the adaptation of Spalax to extreme hypoxia.signal transduction ͉ intracellular trafficking ͉ hypoxia ͉ glycosylation E rythropoietin (EPO) promotes proliferation and differentiation of erythroid cell precursors via activation of its cellsurface receptor (EPO-R) (1, 2). EPO-R is a member of the cytokine-receptor superfamily, characterized by the presence of four conserved Cys residues and a ''WSXWS'' motif in its extracellular domain. The lack of enzymatic activity in the intracellular domain of these receptors necessitates complex formation of ligand-bound receptors with other signaling partners [i.e., Janus kinases (JAKs)] (3) to initiate signaling cascades. EPO-R is synthesized in the endoplasmic reticulum (ER) as a major 64-kDa form with a single endoglycosidase H (Endo H)-sensitive high-mannose oligosaccharide and as a nonglycosylated 62-kDa form. Forty to 60% of the 64-kDa EPO-R molecules undergo further glycan maturation to generate the 66-kDa Endo H-resistant EPO-R (4).In contrast to other type 1 cytokine receptors (5-7), a most striking property of the EPO-R is its low expression on the cell surface (4, 8-10) despite its high intracellular levels. The majority of newly synthesized EPO-R remains sequestered intracellularly and is rapidly degraded (t 1/2 Ϸ 45 min) (11). These metabolic features are similar in both transfected (4) and fetal liver cells that endogenously express the EPO-R (12), suppor...

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In VivoExpression of mRNAs Encoding Hypoxia-Inducible Factor 1

Cited by 382 publications

References 0 publications

Endogenous Erythropoietin as Part of the Cytokine Network in the Pathogenesis of Experimental Autoimmune Encephalomyelitis

Endogenous Erythropoietin as Part of the Cytokine Network in the Pathogenesis of Experimental Autoimmune Encephalomyelitis

Hypoxia-regulated therapeutic gene as a preemptive treatment strategy against ischemia/reperfusion tissue injury

An extracellular region of the erythropoietin receptor of the subterranean blind mole rat Spalax enhances receptor maturation

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