PMC

(A) Serum iron and transferrin saturation rate in mice fed 3.5 ppm iron diet (iron deficient), 35 ppm and 350 ppm iron diets (normal low and normal high iron levels), and 3500 ppm iron diet (iron overload). (B) mRNA levels of EPO by qRT-PCR in kidneys of mice fed different levels of iron diets. (C) mRNA levels of hepcidin by qRT-PCR in livers of mice fed different levels of iron diets. Significantly different among groups compared (n=3) per group.

HF is associated with anemia (low systemic circulatory iron levels) and cardiac tissue iron overload. Low circulatory iron can cause limited functional capacities, so many trials focus on iron supplementation to correct the systemic iron changes. However, HF patients can also have concurrent myocardial iron overload. Increasing cellular and mitochondrial iron contributes to cardiac tissue damage, possibly through a ROS-dependent mechanism. While iron supplementaiton only improves HF symptoms, iron chelation can target tissue iron overload and get to the “heart” of the disease.

In patients in diabetic ketoacidosis (DKA), low pH conditions cause proton-mediated displacement of ferric iron (Fe³⁺) from serum carrier molecules, including transferrin (T). Ferric iron is then reduced at the cell surface to ferrous iron (Fe²⁺). In contrast, deferoxamine (D) directly chelates iron from transferrin, resulting in ferroxamine (iron-deferoxamine complex). Ferroxamine then binds to unidentified receptor(s) on the surface of Zygomycetes. The fungus then liberates the iron from ferroxamine by reduction at the cell surface, solubilizing ferrous iron from ferroxamine. In both cases, ferrous iron is then reoxidized back to ferric iron by copper oxidase (Cu-oxidase). High affinity iron permease (rFTR1), which physically complexes with copper oxidase in yeast, transports ferric iron nearly simultaneously to the oxidation step. Note that the oxidation to ferric iron prior to transport introduces specificity to iron transport by electrochemically separating the trivalent ferric iron from other divalent cations.

WT mice were challenged with intraperitoneal BA injection and 14d later treated with intravenous iron. (A) Hemoglobin levels 24h after the iron treatment in mice fed a regular (black bars) or iron deficient (white bars) diet (regular diet: n = 3, 2-way ANOVA P < 0,0001; ***P = 0.0006: PBS/PBS vs BA/PBS; *P = 0.02: BA/PBS vs BA/iron). (B) Hemoglobin levels 7d after the intravenous iron treatment as in (A) (iron deficient diet: n = 4, 2-way ANOVA P = 0.002; ***P = 0.0007: PBS/PBS vs BA/PBS; **P = 0.003: BA/PBS vs BA/iron). (C) Serum iron levels 24h after intravenous iron treatment in mice on a regular or iron deficient diet (iron deficient diet: n = 4, 2-way ANOVA P = 0.007; **P = 0.006: PBS/PBS vs BA/PBS; **P = 0.006: BA/PBS vs BA/iron). (D) Serum iron levels 7d after intravenous iron treatment as in (C).