Introduction: Pulmonary artery hypertension (PAH) is a devastating and rare disease characterised by restricted flow through the pulmonary arterial circulation resulting in increased pulmonary vascular resistance; which ultimately results in right heart failure and death. Vascular remodelling is hypothesised to be caused by chronic inflammation, disrupted metabolism and dysregulated growth factors leading to endothelial and smooth muscle cell proliferation. Iron deficiency is prevalent in PAH and has been associated with reduced exercise capacity and increase mortality that makes iron deficiency clinically relevant and a potential therapeutic target for PAH. Systematically iron is regulated by the hepcidin/ferroportin axis, hepcidin, described as the global iron regulator, binds to ferroportin, an iron exporter, causing internalisation, thus preventing iron export. Hepcidin has been described to be elevated in patients with idiopathic PAH, therefore the present of this axis has been investigated in human pulmonary endothelial cells (hPAECs) and the manipulation of this axis will lead to iron retention by these cells with consequences that could influence responses locally of other surrounding cells.
Methodology: hPAECs were grown and treated with either hepcidin, IL-6 or haemoglobin. Gene expression was examined by real-time PCR and protein expression by western blot or flow cytometry. hPAECs mediators release was determined by ELISA and proliferation by BrdU and MTS assays. hPAECs and
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human smooth muscle cells (hPASMC) mitochondrial function were examined by the Seahorse assay.
Conclusions: this study present findings that demonstrated the presence of the hepcidin/ferroportin in hPAECs that allows for local iron homeostatic control and modulation of this axis in these cells presents a PAH like phenotype that could contribute to vascular remodelling. Furthermore, IL-6 and hepcidin caused aberrant-BMPR2 signalling, in which BMPR2 protein is downregulated, however downstream signalling of BMPR2 remains active. The results present here here also supports the hypothesis that subclinical haemolysis may have a role in PAH pathophysiology.