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The increase in pulmonary arterial pressure caused by hypoxia depends on iron status

By Thomas G Smith, George M Balanos, Quentin P P Croft, Nick P Talbot, Keith L Dorrington, Peter J Ratcliffe and Peter A Robbins


Hypoxia is a major cause of pulmonary hypertension. Gene expression activated by the transcription factor hypoxia-inducible factor (HIF) is central to this process. The oxygen-sensing iron-dependent dioxygenase enzymes that regulate HIF are highly sensitive to varying iron availability. It is unknown whether iron similarly influences the pulmonary vasculature. This human physiology study aimed to determine whether varying iron availability affects pulmonary arterial pressure and the pulmonary vascular response to hypoxia, as predicted biochemically by the role of HIF. In a controlled crossover study, 16 healthy iron-replete volunteers undertook two separate protocols. The ‘Iron Protocol’ studied the effects of an intravenous infusion of iron on the pulmonary vascular response to 8 h of sustained hypoxia. The ‘Desferrioxamine Protocol’ examined the effects of an 8 h intravenous infusion of the iron chelator desferrioxamine on the pulmonary circulation. Primary outcome measures were pulmonary artery systolic pressure (PASP) and the PASP response to acute hypoxia (ΔPASP), assessed by Doppler echocardiography. In the Iron Protocol, infusion of iron abolished or greatly reduced both the elevation in baseline PASP (P < 0.001) and the enhanced sensitivity of the pulmonary vasculature to acute hypoxia (P = 0.002) that are induced by exposure to sustained hypoxia. In the Desferrioxamine Protocol, desferrioxamine significantly elevated both PASP (P < 0.001) and ΔPASP (P = 0.01). We conclude that iron availability modifies pulmonary arterial pressure and pulmonary vascular responses to hypoxia. Further research should investigate the potential for therapeutic manipulation of iron status in the management of hypoxic pulmonary hypertensive disease

Topics: Respiratory
Publisher: Blackwell Science Inc
OAI identifier:
Provided by: PubMed Central

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  1. (1982). A predictioncorrection scheme for forcing alveolar gases along certain time courses. JA p p lP h y s i o l52,
  2. (2008). Autosomal dominant erythrocytosis and pulmonary arterial hypertension associated with an activating HIF2α mutation.
  3. (1995). Chamber for controlling the end-tidal gas tensions over sustained periods in humans. JA p p lP h y s i o l78,
  4. (1952). Chronic lung disease, polycythemia and congestive heart failure; cardiorespiratory, vascular and renal adjustments in cor pulmonale.
  5. (2006). Concordant regulation of gene expression by hypoxia and 2-oxoglutarate-dependent dioxygenase inhibition: the role of HIF-1α,H I F - 2 α,a n d other pathways.
  6. (2002). Desferrioxamine elevates pulmonary vascular resistance in humans: potential for involvement of HIF-1. JA p p lP h y s i o l 92,
  7. (1993). Desferrioxamine induces erythropoietin gene expression and hypoxia-inducible factor 1 DNA-binding activity: implications for models of hypoxia signal transduction.
  8. (2003). Effect of ascorbate on the activity of hypoxia-inducible factor in cancer cells.
  9. (2000). Effects of desferrioxamine on serum erythropoietin and ventilatory sensitivity to hypoxia in humans. JA p pP h y s i o l 89,
  10. (2006). Endothelin-1, vascular endothelial growth factor and systolic pulmonary artery pressure in patients with Chuvash polycythemia.
  11. (1975). Hemodynamic effects of staged hematocrit reduction in patients with stable cor pulmonale and severely elevated hematocrit levels.
  12. (2003). Heterozygous deficiency of hypoxia-inducible factor-2α protects mice against pulmonary hypertension and right ventricular dysfunction during prolonged hypoxia. JC l i nI n v e s t111,
  13. (2001). HIFα targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing.
  14. (2004). Hydroxylation of HIF-1: oxygen sensing at the molecular level.
  15. (2006). Hypoxic pulmonary vasoconstriction: mechanisms and controversies. JP h y s i o l 570,
  16. (1999). Impaired physiological responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1α. JC l i nI n v e s t103,
  17. (2004). Labile iron in parenteral iron formulations: a quantitative and comparative study.
  18. (2006). Mutation of von Hippel-Lindau tumour suppressor and human cardiopulmonary physiology.
  19. (2007). Non-heme dioxygenases: cellular sensors and regulators jelly rolled into one?
  20. (2001). Partial HIF-1α deficiency impairs pulmonary arterial myocyte electrophysiological responses to hypoxia.
  21. (2002). Pathogenesis of highaltitude pulmonary edema: inflammation is not an etiologic factor.
  22. (1996). Pharmacokinetics of iron (III)-hydroxide sucrose complex after a single intravenous dose in healthy volunteers.
  23. (2007). Prevalence and diagnosis of severe pulmonary hypertension in patients with chronic obstructive pulmonary disease.
  24. (1995). Prognostic factors in COPD patients receiving long-term oxygen therapy. Importance of pulmonary artery pressure.
  25. (2006). Pulmonary arterial hypertension.
  26. (2003). Pulmonary hypertension in chronic obstructive pulmonary disease.
  27. (2002). S c h a r fS M ,I q b a lM ,K e l l e rC
  28. (2005). Separating the direct effect of hypoxia from the indirect effect of changes in cardiac output on the maximum pressure difference across the tricuspid valve in healthy humans.
  29. (2005). Severe pulmonary hypertension and chronic obstructive pulmonary disease.
  30. (2003). Structure of factor-inhibiting hypoxia-inducible factor (HIF) reveals mechanism of oxidative modification of HIF-1α.
  31. (2001). Targeting of HIF-α to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation.
  32. (1965). The acute and chronic effects of phlebotomy on general hemodynamics and pulmonary functions of patients with secondary polycythemia associated with pulmonary emphysema.
  33. (2008). The Authors. Journal compilation C
  34. (1966). The circulation in patients with chronic bronchitis and emphysema at rest and during exercise, with special reference to the influence of changes in blood viscosity and blood volume on the pulmonary circulation. JC l i nI n v e s t45,
  35. (2007). The heart and pulmonary circulation at high altitudes: healthy highlanders and chronic mountain sickness.
  36. (2008). The human side of hypoxia-inducible factor.
  37. (1986). The properties of a turbine device for measuring respiratory volumes in man.
  38. (2006). Understanding hypoxia signalling in cells – a new therapeutic opportunity?
  39. (1955). Vascular adjustments after phlebotomy in polycythemic subjects. JC l i nI n v e s t34,

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