HEPCIDIN AND INTERLEUKIN-6 DOWNREGULATE BMPR2 AND DYSREGULATE BMPR2 DOWNSTREAM PATHWAYS; IMPLICATIONS FOR PULMONARY ARTERY HYPERTENSION

Background Pulmonary Arterial Hypertension (PAH) is a condition resulting from vascular remodelling and elevated pulmonary arterial pressure. Bone Morphogenetic Protein Receptor II (BMPR2) mutations have been strongly associated with heritable forms of PAH. Previous studies have demonstrated that the hepcidin/ferroportin axis acts to downregulate BMPR2 and promote proliferation in pulmonary artery smooth muscle. However, the role of hepcidin on pulmonary artery endothelial cells (PAEC) and BMPR2 downstream pathways is yet to be elucidated. Aims To investigate the influence of Hepcidin/IL-6 on PAEC proliferation, mitochondrial dysfunction, as well as BMPR2 and downstream pathway perturbation. Methods PAECs were treated with Hepcidin-25 (100 ng/mL or 1µg/mL) or Interleukin-6 (IL-6) (1 ng/mL or 10 ng/mL). Proliferation was determined using CyQuant assay, gene transcription was analysed using real-time PCR and protein expression by Western Blot (WB) and Enzyme-linked Immunosorbent Assay (ELISA). Results Hepcidin and IL-6 after 24h treatment cause PAECs to proliferate (n=4; p Conclusions These study findings uncover the complexity of the relationship between hepcidin and BMP-signalling in PAECs. Disruption in iron homeostasis and elevation in hepcidin levels have been reported in PAH populations, thus a role for a dysregulated hepcidin/ferroportin axis and downstream pathway disruption presents a potential mechanism for these observations. Nonetheless, further research is pivotal to fully elucidate the role of hepcidin in disrupting PAEC iron homeostasis and BMP-signalling.