Proceedings of The Physiological Society

Europhysiology 2018 (London, UK) (2018) Proc Physiol Soc 41, C103

Oral Communications

Smooth muscle cell iron homeostasis is autonomously controlled by the hepcidin/ferroportin axis and its disruption leads to pulmonary arterial hypertension

S. Lakhal-Littleton1, A. Crosby2, G. Mohammad1, B. Davies1, P. A. Robbins1

1. University of Oxford, Oxford, United Kingdom. 2. Department of Medicine, University of Cambridge, Cambridge, United Kingdom.


Iron deficiency (ID) is the most common nutritional disorder in the world, leading to anaemia in ~25% of cases. ID is a co-morbidity in chronic heart failure and pulmonary arterial hypertension (PAH). However, the mechanistic link between ID and cardiovascular disease, and the importance, if any, of anaemia in this link remain unclear. Ferroportin (FPN), the only known mammalian iron exporter, releases iron from duodenal enterocytes, splenic macrophages and hepatocytes; the sites of iron absorption, recycling and storage respectively. The liver-derived peptide hepcidin controls systemic iron homeostasis by antagonizing FPN at those sites. Previously, our work in the heart has shown that hepcidin produced locally by cardiomyocytes is required for cell-autonomous control of intracellular iron levels, through action on cardiomyocyte FPN. Furthermore, we demonstrated that disruption of the cardiomyocyte hepcidin/FPN axis, through knock-in of the FPN C326Y isoform (which retains iron export function but is resistant to hepcidin), leads to cardiomyocyte iron depletion and fatal heart failure. Heart failure occurred against a background of normal systemic iron levels and no anaemia1,2. FPN is also present in smooth muscle cells, where its function remains unknown. Aim- To define the function of FPN and of its regulation by hepcidin in smooth muscle cells. Methods- We generated mice with a tamoxifen-inducible smooth muscle-specific knock-in of FPN C326Y(iSM-FPNC326Y). We characterised cardiac function by Cine-MRI and assessed pulmonary vascular function by right heart catheterisation. We also carried out lung histology and assessment of iron indices. Finally, we investigated the effect of intravenous iron administration in this mouse model. Results- iSM-FPNC326Y mice did not differ from controls in terms of blood iron indices. Nonetheless, they showed elevated right ventricle systolic pressure (RVSP) at 6 weeks and 3 months post tamoxifen-injection. This was associated with increased mascularisation of the pulmonary arterioles. Cine-MRI showed increased RV end systolic volume, and reduced RV ejection fraction at both timepoints. These observations are consistent with the development of PAH. Intravenous iron, given at weeks 1, 3 and 5 post-tamoxifen injection prevented the development of PAH at 6 weeks. Conclusion- These data demonstrate, for the first time, that normal pulmonary vascular function requires control of intracellular iron levels in smooth muscle cells, and that this control is dependent on a local FPN/hepcidin axis. Disruption of this local axis leads to PAH against a background of normal systemic iron homeostasis and no anaemia. These data provide a mechanistic explanation for the known link between ID and PAH and for the reported benefits of iron supplementation in this disease setting.

Where applicable, experiments conform with Society ethical requirements