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Title: Iron metabolism and biomarkers in idiopathic pulmonary arterial hypertension
Author: Rhodes, Christopher James
ISNI:       0000 0004 2700 4992
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2011
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Idiopathic pulmonary arterial hypertension (IPAH) is a progressive disease characterised by increased vascular resistance and remodelling of the pulmonary vasculature. This causes strain on the right ventricle, leading eventually to failure and death. Iron status is thought to influence pulmonary vascular tone, particularly in hypoxia, and may be important in IPAH. Proteomic studies of lung tissues from IPAH patients versus control lobectomy samples revealed downregulated levels of the haemoglobin- and haem-scavenging proteins haptoglobin (Hp) and haemopexin. Plasma levels of Hp were also reduced in IPAH and related to the Hp genotype. Consistently low Hp levels were associated with dysregulated iron homeostasis in IPAH patients. Iron deficiency, as defined by raised plasma soluble transferrin receptor (sTfR) levels, was prevalent in IPAH patients and related to increased levels of the master iron regulator hepcidin. Iron deficiency was also associated with poor exercise capacity, disease progression and mortality. Circulating sTfR levels were compared against other iron-related and established prognostic biomarkers in IPAH, including N-terminal brain natriuretic peptide (NT-proBNP), red cell distribution width (RDW), growth differentiation factor-15 and interleukin-6. All predicted survival and related to disease severity in IPAH, but RDW and NT-proBNP provided the most information when clinical and haemodynamic indices were considered. Dysfunctional bone morphogenetic protein (BMP) receptor type II (BMPR2) signalling contributes to idiopathic as well as heritable PAH. Downregulation of BMPR2, but not the other type II BMP receptors ActRIIA and ActRIIB, led to increased hepcidin expression and secretion in response to BMP-6 stimulation in hepatocellular carcinoma HepG2 cells. Hepcidin expression was also enhanced in rat lung tissue following 1 or 2 weeks exposure to hypoxia. In conclusion, dysregulation of iron homeostasis is common in IPAH and appears to be important clinically. Increased hepcidin levels may contribute to this phenomenon and reflect the dysfunctional BMPR2 signalling associated with the disease.
Supervisor: Wilkins, Martin ; Wharton, John Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral