The Hepcidin/Ferroportin axis modulates proliferation of pulmonary artery smooth muscle cells

• Published in: Scientific reports Vol. 8; no. 1; pp. 12972 - 11
• Main Authors: Ramakrishnan, Latha, Pedersen, Sofia L., Toe, Quezia K., West, Laura E., Mumby, Sharon, Casbolt, Helen, Issitt, Theo, Garfield, Benjamin, Lawrie, Allan, Wort, S. John, Quinlan, Gregory J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 28.08.2018; Nature Publishing Group
• Subjects: 13/1; 13/106; 13/21; 13/51; 14/19; 692/4019; 692/4019/592/75/593; 692/699/75/593; Accumulation; Antibodies, Monoclonal - pharmacology; Antigens, CD - metabolism; Antigens, Differentiation, Myelomonocytic - metabolism; Autocrine Communication - drug effects; Autocrine Communication - physiology; Autocrine signalling; Cation Transport Proteins - biosynthesis; CD163 antigen; Cell Proliferation; Cells, Cultured; Excretion; Gene Expression Regulation - drug effects; Gene Expression Regulation - physiology; Haptoglobin; Hemoglobin; Hepcidin; Hepcidins - biosynthesis; Homeostasis; Humanities and Social Sciences; Humans; Hypertension; Interleukin 6; Interleukin-6 - metabolism; Iron; Iron - metabolism; Monoclonal antibodies; multidisciplinary; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - metabolism; Myocytes, Smooth Muscle - cytology; Myocytes, Smooth Muscle - metabolism; Pulmonary arteries; Pulmonary artery; Pulmonary Artery - cytology; Pulmonary Artery - metabolism; Pulmonary hypertension; Receptors, Cell Surface - metabolism; Science; Science (multidisciplinary); Smooth muscle; Transcription; Transcription, Genetic - drug effects; Transcription, Genetic - physiology
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-018-31095-0

Studies were undertaken to examine any role for the hepcidin/ferroportin axis in proliferative responses of human pulmonary artery smooth muscle cells (hPASMCs). Entirely novel findings have demonstrated the presence of ferroportin in hPASMCs. Hepcidin treatment caused increased proliferation of these cells most likely by binding ferroportin resulting in internalisation and cellular iron retention. Cellular iron content increased with hepcidin treatment. Stabilisation of ferroportin expression and activity via intervention with the therapeutic monoclonal antibody LY2928057 reversed proliferation and cellular iron accumulation. Additionally, IL-6 treatment was found to enhance proliferation and iron accumulation in hPASMCs; intervention with LY2928057 prevented this response. IL-6 was also found to increase hepcidin transcription and release from hPASMCs suggesting a potential autocrine response. Hepcidin or IL-6 mediated iron accumulation contributes to proliferation in hPASMCs; ferroportin mediated cellular iron excretion limits proliferation. Haemoglobin also caused proliferation of hPASMCs; in other novel findings, CD163, the haemoglobin/haptoglobin receptor, was found on these cells and offers a means for cellular uptake of iron via haemoglobin. Il-6 was also found to modulate CD163 on these cells. These data contribute to a better understanding of how disrupted iron homeostasis may induce vascular remodelling, such as in pulmonary arterial hypertension.