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Hypoxic regulation of erythropoiesis and iron metabolism.
Haase VH
(2010) Am J Physiol Renal Physiol 299: F1-13
MeSH Terms: Anemia, Animals, Basic Helix-Loop-Helix Transcription Factors, Bone Marrow, Erythrocytes, Erythropoiesis, Erythropoietin, Gene Expression Regulation, Hematinics, Homeostasis, Humans, Hypoxia, Iron, Kidney, Oxygen, Polycythemia, Procollagen-Proline Dioxygenase, Protein Processing, Post-Translational, Von Hippel-Lindau Tumor Suppressor Protein
Show Abstract · Added August 19, 2013
The kidney is a highly sensitive oxygen sensor and plays a central role in mediating the hypoxic induction of red blood cell production. Efforts to understand the molecular basis of oxygen-regulated erythropoiesis have led to the identification of erythropoietin (EPO), which is essential for normal erythropoiesis and to the purification of hypoxia-inducible factor (HIF), the transcription factor that regulates EPO synthesis and mediates cellular adaptation to hypoxia. Recent insights into the molecular mechanisms that control and integrate cellular and systemic erythropoiesis-promoting hypoxia responses and their potential as a therapeutic target for the treatment of renal anemia are discussed in this review.
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19 MeSH Terms
A feedback loop involving the Phd3 prolyl hydroxylase tunes the mammalian hypoxic response in vivo.
Minamishima YA, Moslehi J, Padera RF, Bronson RT, Liao R, Kaelin WG
(2009) Mol Cell Biol 29: 5729-41
MeSH Terms: Animals, Cardiomegaly, Cardiomyopathies, Cell Hypoxia, Enzyme Activation, Feedback, Physiological, Heart Function Tests, Hypoxia-Inducible Factor 1, alpha Subunit, Hypoxia-Inducible Factor-Proline Dioxygenases, Kidney, Liver, Mammals, Mice, Mitochondria, Myocardium, Polycythemia, Procollagen-Proline Dioxygenase, Survival Analysis, Von Hippel-Lindau Tumor Suppressor Protein
Show Abstract · Added March 4, 2015
Hypoxia-inducible factor (HIF), consisting of a labile alpha subunit and a stable beta subunit, is a master regulator of hypoxia-responsive mRNAs. HIF alpha undergoes oxygen-dependent prolyl hydroxylation, which marks it for polyubiquitination by a complex containing the von Hippel-Lindau protein (pVHL). Among the three Phd family members, Phd2 appears to be the primary HIF prolyl hydroxylase. Phd3 is induced by HIF and, based on findings from in vitro studies, may participate in a HIF-regulatory feedback loop. Here, we report that Phd3 loss exacerbates the HIF activation, hepatic steatosis, dilated cardiomyopathy, and premature mortality observed in mice lacking Phd2 alone and produces a closer phenocopy of the changes seen in mice lacking pVHL than the loss of Phd2 alone. Importantly, the degree to which Phd3 can compensate for Phd2 loss and the degree to which the combined loss of Phd2 and Phd3 resembles pVHL loss appear to differ for different HIF-responsive genes and in different tissues. These findings highlight that the responses of different HIF target genes to changes in prolyl hydroxylase activity differ, quantitatively and qualitatively, in vivo and have implications for the development of paralog-specific prolyl hydroxylase inhibitors as therapeutic agents.
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19 MeSH Terms
Somatic inactivation of the PHD2 prolyl hydroxylase causes polycythemia and congestive heart failure.
Minamishima YA, Moslehi J, Bardeesy N, Cullen D, Bronson RT, Kaelin WG
(2008) Blood 111: 3236-44
MeSH Terms: Alleles, Animals, Cells, Cultured, DNA-Binding Proteins, Echocardiography, Enzyme Activation, Erythropoiesis, Gene Expression Regulation, Enzymologic, Heart Failure, Hypoxia-Inducible Factor-Proline Dioxygenases, Immediate-Early Proteins, Mice, Mice, Inbred C57BL, Mice, Transgenic, Phenotype, Polycythemia, Procollagen-Proline Dioxygenase, RNA, Messenger
Show Abstract · Added March 4, 2015
Pharmacologic activation of the heterodimeric HIF transcription factor appears promising as a strategy to treat diseases, such as anemia, myocardial infarction, and stroke, in which tissue hypoxia is a prominent feature. HIF accumulation is normally linked to oxygen availability because an oxygen-dependent posttranslational modification (prolyl hydroxylation) marks the HIFalpha subunit for polyubiquitination and destruction. Three enzymes (PHD1, PHD2, and PHD3) capable of catalyzing this reaction have been identified, although PHD2 (also called Egln1) appears to be the primary HIF prolyl hydroxylase in cell culture experiments. We found that conditional inactivation of PHD2 in mice is sufficient to activate a subset of HIF target genes, including erythropoietin, leading to striking increases in red blood cell production. Mice lacking PHD2 exhibit premature mortality associated with marked venous congestion and dilated cardiomyopathy. The latter is likely the result of hyperviscosity syndrome and volume overload, although a direct effect of chronic, high-level HIF stimulation on cardiac myocytes cannot be excluded.
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18 MeSH Terms
von Hippel-Lindau mutation in mice recapitulates Chuvash polycythemia via hypoxia-inducible factor-2alpha signaling and splenic erythropoiesis.
Hickey MM, Lam JC, Bezman NA, Rathmell WK, Simon MC
(2007) J Clin Invest 117: 3879-89
MeSH Terms: Amino Acid Substitution, Animals, Basic Helix-Loop-Helix Transcription Factors, Disease Models, Animal, Erythropoiesis, Erythropoietin, Genetic Diseases, Inborn, Hematopoiesis, Extramedullary, Humans, Megakaryocytes, Mice, Mice, Mutant Strains, Mutation, Missense, Polycythemia, Signal Transduction, Spleen, Vascular Endothelial Growth Factors, Von Hippel-Lindau Tumor Suppressor Protein
Show Abstract · Added October 17, 2015
The R200W mutation in the von Hippel-Lindau (VHL) tumor suppressor protein (pVHL) is unique in that it is not associated with tumor development, but rather with Chuvash polycythemia, a heritable disease characterized by elevated hematocrit and increased serum levels of erythropoietin and VEGF. Previous studies have implicated hypoxia-inducible factor-1alpha (HIF-1alpha) signaling in this disorder, although the effects of this mutation on pVHL function are not fully understood. In order to explore the mechanisms underlying the development of this polycythemia, we generated mice homozygous for the R200W mutation (Vhl(R/R)). Vhl(R/R) mice developed polycythemia highly similar to the human disease. The activity of HIF proteins, specifically the HIF-2alpha isoform, was upregulated in ES cells and tissues from Vhl(R/R) mice. Furthermore, we observed a striking phenotype in Vhl(R/R) spleens, with greater numbers of erythroid progenitors and megakaryocytes and increased erythroid differentiation of Vhl(R/R) splenic cells in vitro. These findings suggest that enhanced expression of key HIF-2alpha genes promotes splenic erythropoiesis, resulting in the development of polycythemia in Vhl(R/R) mice. This mouse model is a faithful recapitulation of this VHL-associated syndrome and represents a useful tool for studying polycythemias and investigating potential therapeutics.
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18 MeSH Terms
Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs).
Peyssonnaux C, Zinkernagel AS, Schuepbach RA, Rankin E, Vaulont S, Haase VH, Nizet V, Johnson RS
(2007) J Clin Invest 117: 1926-32
MeSH Terms: Albumins, Animals, Antimicrobial Cationic Peptides, Base Sequence, Cation Transport Proteins, Down-Regulation, Gene Deletion, Hepatocytes, Hepcidins, Homeostasis, Humans, Hypoxia-Inducible Factor 1, Integrases, Iron, Liver, Mice, Mice, Inbred C57BL, Mice, Transgenic, Molecular Sequence Data, Polycythemia, Promoter Regions, Genetic, Protein Binding, Up-Regulation, Von Hippel-Lindau Tumor Suppressor Protein
Show Abstract · Added August 19, 2013
Iron is essential for many biological processes, including oxygen delivery, and its supply is tightly regulated. Hepcidin, a small peptide synthesized in the liver, is a key regulator of iron absorption and homeostasis in mammals. Hepcidin production is increased by iron overload and decreased by anemia and hypoxia; but the molecular mechanisms that govern the hepcidin response to these stimuli are not known. Here we establish that the von Hippel-Lindau/hypoxia-inducible transcription factor (VHL/HIF) pathway is an essential link between iron homeostasis and hepcidin regulation in vivo. Through coordinate downregulation of hepcidin and upregulation of erythropoietin and ferroportin, the VHL-HIF pathway mobilizes iron to support erythrocyte production.
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24 MeSH Terms
Hypoxia-inducible factor-2 (HIF-2) regulates hepatic erythropoietin in vivo.
Rankin EB, Biju MP, Liu Q, Unger TL, Rha J, Johnson RS, Simon MC, Keith B, Haase VH
(2007) J Clin Invest 117: 1068-77
MeSH Terms: Animals, Basic Helix-Loop-Helix Transcription Factors, Disease Models, Animal, Erythropoietin, Gene Expression Regulation, Hepatocytes, Liver, Mice, Mice, Knockout, Polycythemia Vera, Von Hippel-Lindau Tumor Suppressor Protein, von Hippel-Lindau Disease
Show Abstract · Added August 19, 2013
Erythropoiesis is critically dependent on erythropoietin (EPO), a glycoprotein hormone that is regulated by hypoxia-inducible factor (HIF). Hepatocytes are the primary source of extrarenal EPO in the adult and express HIF-1 and HIF-2, whose roles in the hypoxic induction of EPO remain controversial. In order to define the role of HIF-1 and HIF-2 in the regulation of hepatic EPO expression, we have generated mice with conditional inactivation of Hif-1alpha and/or Hif-2alpha (Epas1) in hepatocytes. We have previously shown that inactivation of the von Hippel-Lindau tumor suppressor pVHL, which targets both HIFs for proteasomal degradation, results in increased hepatic Epo production and polycythemia independent of Hif-1alpha. Here we show that conditional inactivation of Hif-2alpha in pVHL-deficient mice suppressed hepatic Epo and the development of polycythemia. Furthermore, we found that physiological Epo expression in infant livers required Hif-2alpha but not Hif-1alpha and that the hypoxic induction of liver Epo in anemic adults was Hif-2alpha dependent. Since other Hif target genes such phosphoglycerate kinase 1 (Pgk) were Hif-1alpha dependent, we provide genetic evidence that HIF-1 and HIF-2 have distinct roles in the regulation of hypoxia-inducible genes and that EPO is preferentially regulated by HIF-2 in the liver.
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12 MeSH Terms
Inactivation of the arylhydrocarbon receptor nuclear translocator (Arnt) suppresses von Hippel-Lindau disease-associated vascular tumors in mice.
Rankin EB, Higgins DF, Walisser JA, Johnson RS, Bradfield CA, Haase VH
(2005) Mol Cell Biol 25: 3163-72
MeSH Terms: Animals, Aryl Hydrocarbon Receptor Nuclear Translocator, DNA-Binding Proteins, Erythropoietin, Gene Deletion, Gene Expression, Gene Silencing, Genes, Tumor Suppressor, Hemangioma, Cavernous, Hepatocytes, Hypoxia-Inducible Factor 1, alpha Subunit, Liver, Liver Neoplasms, Mice, Mice, Knockout, Phosphotransferases (Alcohol Group Acceptor), Polycythemia, Receptors, Aryl Hydrocarbon, Transcription Factors, Tumor Suppressor Proteins, Ubiquitin-Protein Ligases, Vascular Endothelial Growth Factor A, Von Hippel-Lindau Tumor Suppressor Protein, von Hippel-Lindau Disease
Show Abstract · Added August 19, 2013
Patients with germ line mutations in the VHL tumor suppressor gene are predisposed to the development of highly vascularized tumors within multiple tissues. Loss of pVHL results in constitutive activation of the transcription factors HIF-1 and HIF-2, whose relative contributions to the pathogenesis of the VHL phenotype have yet to be defined. In order to examine the role of HIF in von Hippel-Lindau (VHL)-associated vascular tumorigenesis, we utilized Cre-loxP-mediated recombination to inactivate hypoxia-inducible factor-1alpha (Hif-1alpha) and arylhydrocarbon receptor nuclear translocator (Arnt) genes in a VHL mouse model of cavernous liver hemangiomas and polycythemia. Deletion of Hif-1alpha did not affect the development of vascular tumors and polycythemia, nor did it suppress the increased expression of vascular endothelial growth factor (Vegf) and erythropoietin (Epo). In contrast, phosphoglycerokinase (Pgk) expression was substantially decreased, providing evidence for target gene-dependent functional redundancy between different Hif transcription factors. Inactivation of Arnt completely suppressed the development of hemangiomas, polycythemia, and Hif-induced gene expression. Here, we demonstrate genetically that the development of VHL-associated vascular tumors in the liver depends on functional ARNT. Furthermore, we provide evidence that individual HIF transcription factors may play distinct roles in the development of specific VHL disease manifestations.
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24 MeSH Terms
Sleep-related hypoxaemia and excessive erythrocytosis in Andean high-altitude natives.
Spicuzza L, Casiraghi N, Gamboa A, Keyl C, Schneider A, Mori A, Leon-Velarde F, Di Maria GU, Bernardi L
(2004) Eur Respir J 23: 41-6
MeSH Terms: Adult, Altitude, Humans, Hypoxia, Indians, South American, Male, Oxygen, Peru, Polycythemia, Polysomnography, Sleep
Show Abstract · Added December 10, 2013
To determine whether nocturnal hypoxaemia contributes to the excessive erythrocytosis (EE) in Andean natives, standard polysomnographies were performed in 10 patients with EE and in 10 controls (mean haematocrit 76.6 +/- 1.3% and 5.4 +/- 0.8%, respectively) living at an altitude of 4,380 m. In addition, the effect of O2 administration for 1 h prior to sleep, and the relationship between the hypoxic/hypercapnic ventilatory response and the apnoea/hypopnoea index (AHI) during sleep were studied. Awake arterial oxygen saturation (Sa,O2) was significantly lower in patients with EE than in controls (83.7 +/- 0.3% versus 85.6 +/- 0.4%). In both groups, the mean Sa,O2 significantly decreased during sleep (to 80.0 +/- 0.8% in EE and to 82.8 +/- 0.5% in controls). The mean Sa,O2 values remained significantly lower in patients with EE than in controls at all times of the night, and patients with EE spent significantly more time than the controls with an Sa,O2 of <80%. There were no differences between the two groups in the number and duration of the apnoeas/hypopnoeas. None of these variables were affected by O2 administration. In both groups the AHI positively correlated with the hypercapnic ventilatory response. Andean natives undergo minor respiratory disorders during sleep. The reduction in oxygen saturation found in subjects with excessive erythrocytosis was small, yet consistent and potentially important, as it remained below the threshold known for the increase in erythropoietin stimulation. This may be an important factor promoting erythropoiesis, but its relevance needs to be further explored.
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11 MeSH Terms
Ventilation, autonomic function, sleep and erythropoietin. Chronic mountain sickness of Andean natives.
Bernardi L, Roach RC, Keyl C, Spicuzza L, Passino C, Bonfichi M, Gamboa A, Gamboa J, Malcovati L, Schneider A, Casiraghi N, Mori A, Leon-Velarde F
(2003) Adv Exp Med Biol 543: 161-75
MeSH Terms: Altitude Sickness, Autonomic Nervous System, Chronic Disease, Circadian Rhythm, Erythropoietin, Humans, Hypoxia, Indians, South American, Peru, Polycythemia, Respiratory Physiological Phenomena, Sleep
Show Abstract · Added December 10, 2013
Polycythemia is one of the key factors involved in the chronic mountain sickness syndrome, a condition frequent in Andean natives but whose causes still remain unclear. In theory, polycythemia may be secondary to abnormalities in ventilation, occurring during day or night (e.g. due to sleep abnormalities) stimulating excessive erythropoietin (Epo) production, or else it may result from either autogenous production, or from co-factors like cobalt. To assess the importance of these points, we studied subjects with or without polycythemia, born and living in Cerro de Pasco (Peru, 4330m asl, CP) and evaluated the relationship between Epo and respiratory variables both in CP and sea level. We also assessed the relationship between sleep abnormalities and the circadian rhythm of Epo. Polycythemic subjects showed higher Epo in all conditions, lower SaO2 and hypoxic ventilatory response, higher physiological dead space and higher CO2, suggesting ventilatory inefficiency. Epo levels could be highly modified by the level of oxygenation, and were related to similar directional changes in SaO2. Cobalt levels were normal in all subjects and correlated poorly with hematologic variables. The diurnal variations in Epo were grossly abnormal in polycythemic subjects, with complete loss of the circadian rhythm. These abnormalities correlated with the levels of hypoxemia during the night, but not with sleep abnormalities, which were only minor even in polycythemic subjects. The increased Epo production is mainly related to a greater ventilatory inefficiency, and not to altered sensitivity to hypoxia, cobalt or sleep abnormalities. Improving oxygenation can represent a possible therapeutic option for this syndrome.
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12 MeSH Terms
Effect of domperidone on ventilation and polycythemia after 5 weeks of chronic hypoxia in rats.
Gamboa J, Macarlupú JL, Rivera-Chira M, Monge-C C, León-Velarde F
(2003) Respir Physiol Neurobiol 135: 1-8
MeSH Terms: Animals, Chronic Disease, Domperidone, Dopamine Antagonists, Hemoglobins, Hypoxia, Male, Polycythemia, Pulmonary Ventilation, Rats, Rats, Sprague-Dawley, Time Factors
Show Abstract · Added May 26, 2016
Chronically hypoxic humans and some mammals have attenuated ventilatory responses, which have been associated with high dopamine level in carotid bodies. Alveolar hypoventilation and blunted ventilatory response have been recognized to be at the basis of Chronic Mountain Sickness by generating arterial hypoxemia and polycythemia. To investigate whether dopamine antagonism could decrease the hemoglobin concentration by stimulating resting ventilation (VE) and/or hypoxic ventilatory response, 18 chronically hypoxic rats (5 weeks, PB=433 Torr) were studied with and without domperidone treatment (a peripheral dopamine antagonist). Acute and prolonged treatment significantly increased poikilocapnic ventilatory response to hypoxia (RVE ml/min/kg=VE at 0.1 FI(O(2))-VE at 0.21 FI(O(2))), from 506+/-36 to 697+/-48; and from 394+/-37 to 660+/-81, respectively. In addition, Domperidone treatment decreased hemoglobin concentration from 21.6+/-0.29 to 18.9+/-0.19 (P<0.01) in rats chronically exposed to hypobaric hypoxia. Our study suggests that the stimulant effect of D(2)-R blockade on ventilatory response to hypoxia seems to compensate the low hypoxic peripheral chemosensitivity after chronic exposure and the latter in turn decrease hemoglobin concentration.
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12 MeSH Terms