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Intravenous iron loading inhibits the pulmonary vascular response to hypoxia in humans
Author(s) -
Smith Thomas G.,
Croft Quentin P.,
Dorrington Keith L.,
Robbins Peter A.
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a1438-a
Subject(s) - hypoxia (environmental) , medicine , hypoxic ventilatory response , in vivo , pulmonary hypertension , hypoxia inducible factors , hif1a , pharmacology , endocrinology , biology , chemistry , respiratory system , oxygen , biochemistry , angiogenesis , organic chemistry , microbiology and biotechnology , gene
Aim: To manipulate the hypoxia‐inducible factor (HIF) transcription factors pharmacologically and thereby confirm that HIF regulates human pulmonary vascular responses to hypoxia. Background: HIF controls intracellular responses to hypoxia, and our recent work strongly implicates HIF in regulating human heart/lung physiology (Smith et al. PLoS Med 2006; 3 : ). Iron is an obligate co‐factor in the degradation pathway through which HIF is primarily regulated, and iron supplementation potentiates HIF degradation in vitro . Hypothesis: Supraphysiological levels of iron similarly augment HIF degradation in vivo and thus inhibit acclimatisation to hypoxia. Methods: Six normal subjects were each studied on two days. Day 1 (control) began with an infusion of saline while on Day 2 it was 200 mg iron sucrose. On each day subjects then underwent: a 40‐min acute isocapnic hypoxia protocol (end‐tidal PO 2 50 mmHg), with pulmonary vascular tone assessed echocardiographically; 8 h of isocapnic hypoxia in a chamber; repeat of the acute hypoxia protocol.Results: Iron loading prevented the rise in pulmonary arterial pressure normally present after sustained hypoxia and blunted acclimatisation of the acute hypoxic pulmonary vasoconstrictive response ( p < 0.01; Fig 1). Conclusions: HIF degradation is limited by physiological levels of iron, and HIF appears to control human pulmonary vascular responses to hypoxia. Funded by the Wellcome Trust. TGS is supported by a Rhodes Scholarship.