Carotid body hyperplasia and enhanced ventilatory responses to hypoxia in mice with heterozygous deficiency of PHD2

•  Arterial hypoxaemia leads to a rapid increase in ventilation. If the hypoxaemia is sustained, a further increase in ventilation develops over hours to days in a process termed ventilatory acclimatisation. •  Studies in transgenic mice implicate the hypoxia‐inducible factor (HIF) pathway in the latter process. •  The aim of this study was to investigate the role of HIF prolyl hydroxylase (PHD) enzymes in ventilatory acclimatisation. •  We find that PHD2+/−, but not PHD1−/− or PHD3−/−, mice mimic chronic hypoxia in exhibiting exaggerated ventilatory responses to acute hypoxia. This was associated with carotid body overgrowth. However, use of a PHD inhibitor (PHI) induced both hypoxic ventilatory sensitivity and carotid body proliferation only marginally despite strongly inducing erythropoiesis. •  Taken together, these findings implicate HIF/PHD2 in ventilatory control and carotid body biology but highlight the difficulty of translation from genetic models to pharmacological intervention.

[1]  P. Ratcliffe,et al.  Hyperplasia of pulmonary neuroepithelial bodies (NEB) in lungs of prolyl hydroxylase -1(PHD-1) deficient mice. , 2012, Advances in experimental medicine and biology.

[2]  G. Schley,et al.  Selective stabilization of HIF-1α in renal tubular cells by 2-oxoglutarate analogues. , 2012, The American journal of pathology.

[3]  G. Semenza,et al.  Adaptive and maladaptive cardiorespiratory responses to continuous and intermittent hypoxia mediated by hypoxia-inducible factors 1 and 2. , 2012, Physiological reviews.

[4]  G. Schley,et al.  The protective effect of prolyl-hydroxylase inhibition against renal ischaemia requires application prior to ischaemia but is superior to EPO treatment. , 2012, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[5]  Akane Kawamura,et al.  Inhibition of 2‐Oxoglutarate Dependent Oxygenases , 2011 .

[6]  Jiannis Ragoussis,et al.  High-resolution genome-wide mapping of HIF-binding sites by ChIP-seq. , 2011, Blood.

[7]  Thomas G. Smith,et al.  Cardiopulmonary function in two human disorders of the hypoxia-inducible factor (HIF) pathway: von Hippel-Lindau disease and HIF-2α gain-of-function mutation , 2011, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[8]  P. Ratcliffe,et al.  Differential Sensitivity of Hypoxia Inducible Factor Hydroxylation Sites to Hypoxia and Hydroxylase Inhibitors* , 2011, The Journal of Biological Chemistry.

[9]  G. Semenza,et al.  Hypoxia-inducible factor 2α (HIF-2α) heterozygous-null mice exhibit exaggerated carotid body sensitivity to hypoxia, breathing instability, and hypertension , 2011, Proceedings of the National Academy of Sciences.

[10]  R. Schmieder,et al.  Inhibition of prolyl hydroxylases increases erythropoietin production in ESRD. , 2010, Journal of the American Society of Nephrology : JASN.

[11]  J. Hale,et al.  Prolyl hydroxylase domain-containing protein inhibitors as stabilizers of hypoxia-inducible factor: small molecule-based therapeutics for anemia , 2010, Expert opinion on therapeutic patents.

[12]  B. Brüne,et al.  Roles of hypoxia‐inducible factor‐1α (HIF‐1α) versus HIF‐2α in the survival of hepatocellular tumor spheroids , 2010, Hepatology.

[13]  Robert A. Harris,et al.  Loss or silencing of the PHD1 prolyl hydroxylase protects livers of mice against ischemia/reperfusion injury. , 2010, Gastroenterology.

[14]  Frederik De Smet,et al.  Heterozygous Deficiency of PHD2 Restores Tumor Oxygenation and Inhibits Metastasis via Endothelial Normalization , 2009, Cell.

[15]  P. Carmeliet,et al.  Inhibition of oxygen sensors as a therapeutic strategy for ischaemic and inflammatory disease , 2009, Nature Reviews Drug Discovery.

[16]  W. Kaelin,et al.  Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. , 2008, Molecular cell.

[17]  P. Carmeliet,et al.  Abnormal Sympathoadrenal Development and Systemic Hypotension in PHD3−/− Mice , 2008, Molecular and Cellular Biology.

[18]  Robert A. Harris,et al.  Deficiency or inhibition of oxygen sensor Phd1 induces hypoxia tolerance by reprogramming basal metabolism , 2008, Nature Genetics.

[19]  J. López-Barneo,et al.  Glia-like Stem Cells Sustain Physiologic Neurogenesis in the Adult Mammalian Carotid Body , 2007, Cell.

[20]  P. Robbins.  Role of the peripheral chemoreflex in the early stages of ventilatory acclimatization to altitude , 2007, Respiratory Physiology & Neurobiology.

[21]  J. Tisdale,et al.  HIF prolyl hydroxylase inhibition results in endogenous erythropoietin induction, erythrocytosis, and modest fetal hemoglobin expression in rhesus macaques. , 2007, Blood.

[22]  J. López-Barneo,et al.  Mechanisms of acute oxygen sensing by the carotid body: Lessons from genetically modified animals , 2007, Respiratory Physiology & Neurobiology.

[23]  G. Semenza,et al.  Heterozygous HIF‐1α deficiency impairs carotid body‐mediated systemic responses and reactive oxygen species generation in mice exposed to intermittent hypoxia , 2006, The Journal of physiology.

[24]  I. Homma,et al.  Impaired ventilation and metabolism response to hypoxia in histamine H1 receptor-knockout mice , 2006, Respiratory Physiology & Neurobiology.

[25]  Å. Borg,et al.  Recruitment of HIF-1alpha and HIF-2alpha to common target genes is differentially regulated in neuroblastoma: HIF-2alpha promotes an aggressive phenotype. , 2006, Cancer cell.

[26]  K. Takeda,et al.  Placental but Not Heart Defects Are Associated with Elevated Hypoxia-Inducible Factor α Levels in Mice Lacking Prolyl Hydroxylase Domain Protein 2 , 2006, Molecular and Cellular Biology.

[27]  Thomas G. Smith,et al.  Mutation of von Hippel–Lindau Tumour Suppressor and Human Cardiopulmonary Physiology , 2006, PLoS medicine.

[28]  N. Prabhakar,et al.  Cellular and molecular mechanisms associated with carotid body adaptations to chronic hypoxia. , 2005, High altitude medicine & biology.

[29]  Patrick H. Maxwell,et al.  Contrasting Properties of Hypoxia-Inducible Factor 1 (HIF-1) and HIF-2 in von Hippel-Lindau-Associated Renal Cell Carcinoma , 2005, Molecular and Cellular Biology.

[30]  A. Harris,et al.  Differential Function of the Prolyl Hydroxylases PHD1, PHD2, and PHD3 in the Regulation of Hypoxia-inducible Factor* , 2004, Journal of Biological Chemistry.

[31]  Brian Keith,et al.  Differential Roles of Hypoxia-Inducible Factor 1α (HIF-1α) and HIF-2α in Hypoxic Gene Regulation , 2003, Molecular and Cellular Biology.

[32]  Kan Ding,et al.  Multiple organ pathology, metabolic abnormalities and impaired homeostasis of reactive oxygen species in Epas1−/− mice , 2003, Nature Genetics.

[33]  J. Pouysségur,et al.  HIF prolyl‐hydroxylase 2 is the key oxygen sensor setting low steady‐state levels of HIF‐1α in normoxia , 2003, The EMBO journal.

[34]  G. Semenza,et al.  Defective carotid body function and impaired ventilatory responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1α , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[35]  J. Peng,et al.  The transcription factor EPAS-1/hypoxia-inducible factor 2alpha plays an important role in vascular remodeling. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[36]  G. Semenza,et al.  Defective vascularization of HIF-1alpha-null embryos is not associated with VEGF deficiency but with mesenchymal cell death. , 1999, Developmental biology.

[37]  R. Hammer,et al.  The hypoxia-responsive transcription factor EPAS1 is essential for catecholamine homeostasis and protection against heart failure during embryonic development. , 1998, Genes & development.

[38]  M. Gassmann,et al.  Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha. , 1998, Genes & development.

[39]  P. Robbins,et al.  Ventilatory response to 8 h of isocapnic and poikilocapnic hypoxia in humans. , 1995, Journal of applied physiology.

[40]  S. Lahiri,et al.  A morphometric study of the carotid body in chronically hypoxic rats. , 1984, Journal of applied physiology: respiratory, environmental and exercise physiology.

[41]  P. Laidler,et al.  Hypoxia and the carotid body. , 1977, Journal of clinical pathology. Supplement.

[42]  P. Laidler,et al.  A quantitative morphological study of the carotid bodies of rats living at a simulated altitude of 4300 metres , 1975, The Journal of pathology.

[43]  S. Udenfriend,et al.  Prolyl hydroxylase. , 1974, Advances in enzymology and related areas of molecular biology.

[44]  Å. Borg,et al.  Recruitment of HIF-1 a and HIF-2 a to common target genes is differentially regulated in neuroblastoma : HIF-2 a promotes an aggressive phenotype , 2022 .