mRNA regulation of cardiac iron transporters and ferritin subunits in a mouse model of iron overload

Abstract

Iron cardiomyopathy is the leading cause of death in iron overload. Men have twice the mortality rate of women, though the cause is unknown. In hemojuvelin-knockout mice, a model of the disease, males load more cardiac iron than females. We postulated that sex differences in cardiac iron import cause differences in cardiac iron concentration. RT-PCR was used to measure mRNA of cardiac iron transporters in hemojuvelin-knockout mice. No sex differences were discovered among putative importers of non-transferrin bound iron (L-type and T-type calcium channels, ZRT/IRT-like protein 14 zinc channels). Transferrin-bound iron transporters were also analyzed; these are controlled by the iron regulatory element/iron regulatory protein (IRE/IRP) system. There was a positive relationship between cardiac iron and ferroportin mRNA in both sexes, but it was significantly steeper in females (p<0.05). Transferrin receptor 1 and divalent metal transporter 1 were more highly expressed in females than males (p<0.01 and p<0.0001, respectively), consistent with their lower cardiac iron levels, as predicted by IRE/IRP regulatory pathways. Light-chain (L) ferritin showed a positive correlation with cardiac iron that was nearly identical in males and females (R2=0.41, p<0.01 and R2=0.56, p<0.05, respectively), while heavy-chain (H) ferritin was constitutively expressed in both sexes. This represents the first report of IRE/IRP regulatory pathways in the heart. Transcriptional regulation of ferroportin was suggested in both sexes, creating a potential mechanism for differential set points for iron export. Constitutive H-ferritin expression suggests a logical limit to cardiac iron buffering capacity at levels known to produce heart failure in humans.

Combined treatment of 3-hydroxypyridine-4-one derivatives and green tea extract to induce hepcidin expression in iron-overloaded β-thalassemic mice

“…Plasma ALT activity, plasma NTBI concentrations and liver iron accumulation in the BKO-N diet mice were not much different from those in the WT-N diet mice, whereas levels of these parameters were considerably increased in the BKO-Fe diet mice. Some other groups have demonstrated that mRNA expressions of iron-regulatory proteins such as hepcidin, ferroportin, and transferrin receptors vary between the genders of the mice [37,38]. However, we did not find any difference in hepatic Hamp1 mRNA expression between male and female of WT and BKO mice in this study.…”

Serum ferritin and risk for new‐onset heart failure and cardiovascular events in the community

“…Additional literature also suggests that the link between ferritin, hepcidin, and dysmetabolic features may be particularly relevant in women . The role of sex hormones in the regulation of ferritin and hepcidin expression may also be responsible to a certain extent for the sex‐related differences observed in the present study and has recently been studied in animal models . Yet, although we adjusted for menopausal status and other established CV/metabolic risk factors, levels of ferritin remained associated with incident HF in women.…”

Estimating tissue iron burden: current status and future prospects

“…The biology of serum ferritin is poorly understood. Ferritin is primarily an intracellular protein produced to protect cells from labile intracellular iron (Brewer et al, 2014). Most of the circulating Patients were undergoing routine clinical assessment of cardiac T2* and LIC at 1-to 2-year intervals.…”