The hepcidin-ferroportin axis influences mitochondrial function, proliferation, and migration in pulmonary artery endothelial and smooth muscle cells.

Autor: Issitt T; NHLI, Faculty of Medicine Imperial College London London UK., Toe QK; NHLI, Faculty of Medicine Imperial College London London UK., Pedersen SL; NHLI, Faculty of Medicine Imperial College London London UK., Shackshaft T; NHLI, Faculty of Medicine Imperial College London London UK., Ghazaly MM; NHLI, Faculty of Medicine Imperial College London London UK.; Institute of Tropical Biodiversity and Sustainable Development Univerity of Malaysia Terengganu Malaysia., West L; Department of Infection, Immunity & Cardiovascular Disease University of Sheffield Sheffield UK., Arnold ND; Department of Infection, Immunity & Cardiovascular Disease University of Sheffield Sheffield UK., Mahomed A; NHLI, Faculty of Medicine Imperial College London London UK., Kagugube GW; NHLI, Faculty of Medicine Imperial College London London UK., Ramakrishnan L; NHLI, Faculty of Medicine Imperial College London London UK., Lawrie A; NHLI, Faculty of Medicine Imperial College London London UK., Quinlan GJ; NHLI, Faculty of Medicine Imperial College London London UK., Wort SJ; NHLI, Faculty of Medicine Imperial College London London UK.; Royal Brompton Hospital Adult Centre for Pulmonary Hypertension London UK.
Jazyk: angličtina
Zdroj: Pulmonary circulation [Pulm Circ] 2024 Dec 18; Vol. 14 (4), pp. e70006. Date of Electronic Publication: 2024 Dec 18 (Print Publication: 2024).
DOI: 10.1002/pul2.70006
Abstrakt: Elevated circulating hepcidin levels have been reported in patients with pulmonary artery hypertension (PAH). Hepcidin has been shown to promote proliferation of human pulmonary artery smooth muscle cells (PASMCs) in vitro, suggesting a potential role in PAH pathogenesis. However, the role of human pulmonary artery endothelial cells (PAECs) as either a source of hepcidin, or the effect of hepcidin on PAEC function is not as well described. The objective of this study was to define the role of the hepcidin-ferroportin axis on the phenotype of PAEC and to study potential PAEC-PASMC interactions relevant to the pathogenesis of pulmonary vascular remodeling and PAH. PAECs treated with hepcidin, or interleukin-6 were investigated for both ferroportin and hepcidin release and regulation using immunofluorescence, mRNA levels and cellular release assays. Effects of hepcidin on PASMC and PAEC mitochondrial function was investigated using immunofluorescence and seahorse assay. Migration and proliferation of PASMCs treated with conditioned media from hPAEC treated with hepcidin was investigated using the xCELLigence system and other tools. We demonstrate in this study that PAECs express ferroportin; hepcidin treatment of PAECs resulted in mitochondrial iron accumulation and intracellular hepcidin biosynthesis and release. Conditioned media from hepcidin treated PAECs caused PASMCs to down-regulate ferroportin expression whilst promoting migration and proliferation. Inhibition of hepcidin in PAEC conditioned media limited these responses. PASMC cellular and mitochondrial iron retention are associated with migratory and proliferative responses. This study confirms that the hepcidin ferroportin axis is present and operational in PAECs. Modulation of this axis shows distinct differences in responses seen between PAECS and PASMCs. Stimulation of this axis in PAECs with hepcidin may well institute proliferative and migratory responses in PASMCs of relevance to pathogenesis of PAH offering potential novel therapeutic targets.
Competing Interests: The authors declare no conflict of interests.
(© 2024 The Authors. Pulmonary Circulation published by Wiley Periodicals LLC on behalf of the Pulmonary Vascular Research Institute.)
Databáze: MEDLINE
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