Abstract
Iron deficiency augments hypoxic pulmonary arterial pressure in healthy individuals and exacerbates pulmonary arterial hypertension (PAH) in patients, even without anemia. Conversely, iron supplementation has been shown to be beneficial in both settings. The mechanisms underlying the effects of iron availability are not known, due to lack of understanding of how cells of the pulmonary vasculature respond to changes in iron levels. The iron export protein ferroportin (FPN) and its antagonist peptide hepcidin control systemic iron levels by regulating release from the gut and spleen, the sites of absorption and recycling, respectively. We found FPN to be present in pulmonary arterial smooth muscle cells (PASMCs) and regulated by hepcidin cell autonomously. To interrogate the importance of this regulation, we generated mice with smooth muscle-specific knock in of the hepcidin-resistant isoform fpn C326Y. While retaining normal systemic iron levels, this model developed PAH and right heart failure as a consequence of intracellular iron deficiency and increased expression of the vasoconstrictor endothelin-1 (ET-1) within PASMCs. PAH was prevented and reversed by i.v. iron and by the ET receptor antagonist BQ-123. The regulation of ET-1 by iron was also demonstrated in healthy humans exposed to hypoxia and in PASMCs from PAH patients with mutations in bone morphogenetic protein receptor type II. Such mutations were further associated with dysregulation of the HAMP/FPN axis in PASMCs. This study presents evidence that intracellular iron deficiency specifically within PASMCs alters pulmonary vascular function. It offers a mechanistic underpinning for the known effects of iron availability in humans.
Highlights
Iron deficiency augments hypoxic pulmonary arterial pressure in healthy individuals and exacerbates pulmonary arterial hypertension (PAH) in patients, even without anemia
Cellular iron homeostasis is controlled by the iron regulatory proteins (IRP), which controls the levels of iron uptake proteins such as transferrin receptor 1 (TfR1) and divalent metal transporter 1 (DMT1), the iron storage protein ferritin, and in some cells the iron export protein ferroportin (FPN) [14, 15]
The major finding of the current study is that intracellular iron deficiency in pulmonary arterial smooth muscle cells (PASMCs), caused by dysregulation of their FPN, leads to PAH and right heart failure
Summary
Iron deficiency augments hypoxic pulmonary arterial pressure in healthy individuals and exacerbates pulmonary arterial hypertension (PAH) in patients, even without anemia. The regulation of ET-1 by iron was demonstrated in healthy humans exposed to hypoxia and in PASMCs from PAH patients with mutations in bone morphogenetic protein receptor type II Such mutations were further associated with dysregulation of the HAMP/ FPN axis in PASMCs. This study presents evidence that intracellular iron deficiency within PASMCs alters pulmonary vascular function. Data acquired during a previous study of a mouse model of the iron overload disease hemochromatosis, generated through a ubiquitous knock in (KI) of the fpnC326Y gene (which encodes a hepcidin-resistant FPN), revealed that FPN was markedly up-regulated in PASMCs compared with lungs from wild-type control mice (SI Appendix, Fig. S1A). Our study shows that iron deficiency within these cells is sufficient to cause PAH, even against a background of normal iron levels in other tissues
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