![]() ![]() ![]() Our goal was to identify generic mechanisms relevant to the vasculature, and not to focus on a specific vascular bed. The study objective, to determine whether low iron treatments could modify endothelial cells, was achieved using RNA sequencing and validation studies in normal primary human endothelial cells. We hypothesized that treatment-induced transient rises in circulating iron may result in subtle endothelial changes. However, in a survey of HHT patients, approximately 1 in 20 using iron tablets (35/732 (4.8%)) or infusions (24/361 (6.7%)) reported that nosebleeds were worse after iron treatments (manuscript in review). Increasing iron intake through oral and intravenous routes is a key component of HHT patient management in order to replace hemorrhagic iron losses, and avoid or treat iron deficiency. Individuals within a large iron-using population who are able to report vascular sequelae virtually in real-time suggested that there may be clinically relevant consequences: Patients with hereditary hemorrhagic telangiectasia (HHT ) have recurrent nosebleeds that often occur daily. Although most of the circulating iron is bound to transferrin and other proteins, plasma concentrations of non transferrin bound iron (NTBI) may reach or exceed 10μM for several hours following an iron tablet, or infusion, and there are no data to suggest such levels are biologically inert. After conventional iron treatments, serum iron concentrations have been shown to increase acutely, and by 30μmol/L or more in two hours in a proportion of individuals (Shovlin et al, manuscript in review ), with variability explained by activity of the hepcidin/ferroportin axes, and dietary modifiers of iron absorption. The question which we wished to address regarded much lower iron concentrations, of magnitudes encountered following currently recommended treatments for iron deficiency anemia, and/or ingestion of iron supplements bought without medical prescriptions. ![]() In keeping with this, exposure of endothelial cells to very high iron concentrations (30–100μM) results in oxidative stress, apoptosis, proinflammatory, and prothrombotic responses. Iron overload states such as hemochromatosis, and transfusion–requiring hemoglobinopathies result in vascular dysfunction and disease. Iron is essential for numerous processes involved in oxygen transport, storage, and utilization, but high concentrations are profoundly deleterious to cells. This was accompanied by a brisk DNA damage response pulse, as ascertained by the development of DNA damage response (DDR) foci, and p53 stabilization. Comet assays demonstrated that 10μM iron treatment elicited DNA damage within 1 hour. After 1 hour, differentially expressed genes clustered to vesicle mediated transport, protein catabolism, and cell cycle (Benjamini p = 0.0016, 0.0024 and 0.0032 respectively), and by 6 hours, to cellular response to DNA damage stimulus most significantly through DNA repair genes FANCG, BLM, and H2AFX. Clustering for Gene Ontology (GO) performed on all differentially expressed genes revealed significant differences in biological process terms between iron and media-treated EC, whereas 10 sets of an equivalent number of randomly selected genes from the respective EC gene datasets showed no significant differences in any GO terms. Rapid changes in RNA transcript profiles were observed in endothelial cells treated with 10μmol/L iron (II) citrate, compared to media-treated cells. ![]()
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