Iron is essential to the cell. Both iron deficiency and overload impinge negatively on cardiac health. Thus, effective iron homeostasis is important for cardiac function. Ferroportin (FPN), the only known mammalian iron-exporting protein, plays an essential role in iron homeostasis at the systemic level. It increases systemic iron availability by releasing iron from the cells of the duodenum, spleen, and liver, the sites of iron absorption, recycling, and storage respectively. However, FPN is also found in tissues with no known role in systemic iron handling, such as the heart, where its function remains unknown. To explore this function, we generated mice with a cardiomyocyte-specific deletion of Fpn. We show that these animals have severely impaired cardiac function, with a median survival of 22 wk, despite otherwise unaltered systemic iron status. We then compared their phenotype with that of ubiquitous hepcidin knockouts, a recognized model of the iron-loading disease hemochromatosis. The phenotype of the hepcidin knockouts was far milder, with normal survival up to 12 mo, despite far greater iron loading in the hearts. Histological examination demonstrated that, although cardiac iron accumulates within the cardiomyocytes of Fpn knockouts, it accumulates predominantly in other cell types in the hepcidin knockouts. We conclude, first, that cardiomyocyte FPN is essential for intracellular iron homeostasis and, second, that the site of deposition of iron within the heart determines the severity with which it affects cardiac function. Both findings have significant implications for the assessment and treatment of cardiac complications of iron dysregulation. Significance The iron-exporting protein ferroportin is recognized as central to systemic iron regulation, but its role in tissues other than those involved in iron handling is unknown. This study shows that ferroportin expression in cardiomyocytes is essential to intracellular iron homeostasis and to normal cardiac function. It also demonstrates that the site of iron accumulation in the iron-overloaded heart depends on whether ferroportin is expressed in the cardiomyocytes. It further shows that the functional significance of cardiac iron overload is highly dependent upon the site of iron accumulation. These findings change our understanding of intracellular iron homeostasis and have significant implications for the clinical management of cardiac dysfunction associated with iron imbalance.

Hepcidin is the master regulator of systemic iron homeostasis. Derived primarily from the liver, it inhibits the iron exporter ferroportin in the gut and spleen, the sites of iron absorption and recycling respectively. Recently, we demonstrated that ferroportin is also found in cardiomyocytes, and that its cardiac-specific deletion leads to fatal cardiac iron overload. Hepcidin is also expressed in cardiomyocytes, where its function remains unknown. To define the function of cardiomyocyte hepcidin, we generated mice with cardiomyocyte-specific deletion of hepcidin, or knock-in of hepcidin-resistant ferroportin. We find that while both models maintain normal systemic iron homeostasis, they nonetheless develop fatal contractile and metabolic dysfunction as a consequence of cardiomyocyte iron deficiency. These findings are the first demonstration of a cell-autonomous role for hepcidin in iron homeostasis. They raise the possibility that such function may also be important in other tissues that express both hepcidin and ferroportin, such as the kidney and the brain.

Ironing out the details of mucosal healing: Anemia is a frequent complication of disorders such as inflammatory bowel disease, occurring in part as a result of increased bleeding into the intestine. Bessman et al. show that the peptide hormone hepcidin, which regulates systemic iron homeostasis, is required for intestinal repair in a mouse model of inflammatory bowel disease (see the Perspective by Rescigno). This effect was independent of hepatocyte-produced hepcidin and systemic iron levels. Instead, production of hepcidin by conventional dendritic cells was necessary and sufficient to promote local iron sequestration by macrophages, which in turn modulated the makeup of the gut microbiota to one with a more beneficial distribution of species. Science , this issue p. 186 ; see also p. 129

Significance: Pulmonary arterial hypertension (PAH) is a disease in which lung blood pressure is raised chronically, causing right heart failure. It has been shown that iron deficiency also raises lung blood pressure. However, we don’t know the mechanisms because we don’t understand precisely how cells of the lung blood vessels are affected by iron levels. The smooth muscle cells of the lung blood vessels are important for controlling lung blood pressure. Our study shows that iron deficiency specifically within these cells is sufficient to cause PAH, even against a background of normal iron levels in other tissues.

Heart disease is a common manifestation in conditions of iron imbalance. Normal heart function requires coupling of iron supply for oxidative phosphorylation and redox signalling with tight control of intracellular iron to below levels at which excessive ROS are generated. Iron supply to the heart is dependent on systemic iron availability which is controlled by the systemic hepcidin/ferroportin axis. Intracellular iron in cardiomyocytes is controlled in part by the iron regulatory proteins IRP1/2. This mini-review summarises current understanding of how cardiac cells regulate intracellular iron levels, and of the mechanisms linking cardiac dysfunction with iron imbalance. It also highlights a newly-recognised mechanism of intracellular iron homeostasis in cardiomyocytes, based on a cell-autonomous cardiac hepcidin/ferroportin axis. This new understanding raises pertinent questions on the interplay between systemic and local iron control in the context of heart disease, and the effects on heart function of therapies targeting the systemic hepcidin/ferroportin axis.

Iron deficiency is present in ~50% of heart failure (HF) patients. Large multicenter trials have shown that treatment of iron deficiency with i.v. iron benefits HF patients, but the underlying mechanisms are not known. To investigate the actions of iron deficiency on the heart, mice were fed an iron-depleted diet, and some received i.v. ferric carboxymaltose (FCM), an iron supplementation used clinically. Iron-deficient animals became anemic and had reduced ventricular ejection fraction measured by magnetic resonance imaging. Ca ²⁺ signaling, a pathway linked to the contractile deficit in failing hearts, was also significantly affected. Ventricular myocytes isolated from iron-deficient animals produced smaller Ca ²⁺ transients from an elevated diastolic baseline but had unchanged sarcoplasmic reticulum (SR) Ca ²⁺ load, trigger L-type Ca ²⁺ current, or cytoplasmic Ca ²⁺ buffering. Reduced fractional release from the SR was due to downregulated RyR2 channels, detected at protein and message levels. The constancy of diastolic SR Ca ²⁺ load is explained by reduced RyR2 permeability in combination with right-shifted SERCA activity due to dephosphorylation of its regulator phospholamban. Supplementing iron levels with FCM restored normal Ca ²⁺ signaling and ejection fraction. Thus, 2 Ca ²⁺ -handling proteins previously implicated in HF become functionally impaired in iron-deficiency anemia, but their activity is rescued by i.v. iron supplementation.