Arnold, N. D. | bioRxiv Science

bioRxiv2023

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

RationaleElevated 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 PAECfunction has not previously been described. ObjectiveTo define the role of the hepcidin-ferroportin axis on the phenotype of pulmonary artery endothelial cells Methods and resultsPAECs treated with hepcidin, or IL-6 were investigated for both ferroportin and hepcidin release and regulation with 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 PASMC treated with conditioned media from hPAEC treated with hepcidin was investigated using the Xcelligence system and other tools. PAECs express ferroportin; hepcidin treatment of PAECs results in mitochondrial iron accumulation and intracellular hepcidin biosynthesis and release. Conditioned media from hepcidin treated PAECs causes PASMCs to down regulate ferroportin expression whilst promoting migration and proliferation. Inhibition of hepcidin in PAEC conditioned media limits these responses. PASMC cellular and mitochondrial iron retention are associated with migratory and proliferative responses. ConclusionsThe 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 a potential therapeutic target.

cell biology↗

bioRxiv2020

Feasibility and safety of a telemetric pulmonary artery pressure monitoring system in acute and chronic porcine models of pulmonary hypertension.

AimsPulmonary hypertension (PH) is associated with significant morbidity and mortality and leads to progressive right heart failure. In patients with PAH, haemodynamic parameters measured at catheterisation relate to clinical worsening events, in patients with heart failure proactive pulmonary artery pressure based therapeutic intervention reduces hospitalisation. We therefore investigated use of a novel implanted pulmonary artery (PA) pressure monitor to detect clinically relevant changes in pressure in large animal models of pulmonary hypertension (PH). Methods and ResultsPrototype pulmonary artery pressure sensors (Endotronix) were implanted using standard interventional techniques. Acute PH was induced by infusion of thromboxane A2 in domestic swine. Over a physiological range pressure monitors remained concordant to reference catheter (bias -0.43, 95%CI-5.3-4.4). Chronic PH was induced by i.p. injection of monocrotaline. Implanted pressure sensors demonstrated a gradual rise in PA pressure over 30 days (baseline: 20.7+/-0.4 vrs day-30: 31.74+/-1.4, p<0.01). Pressure sensor derived readings matched reference catheter at baseline and day-30. Pressure sensors remained stable and no adverse events were identified by clinical and histological examination. ConclusionsThe development of PA pressure monitors provide long-term haemodynamic data that identified clinically meaningful changes in pulmonary artery pressure. In addition to proactive heart failure management, such devices may be used to optimise or personalize patient therapy, investigate aspects of physiology and pathology essential to the understanding of disease and provide the opportunity to assess therapeutic interventions in clinical studies.

physiology↗