Iron Metabolism in Cardiovascular Disease: Physiology, Mechanisms, and Therapeutic Targets

Abstract

The cardiovascular system requires iron to maintain its high energy demands and metabolic activity. Iron plays a critical role in oxygen transport and storage, mitochondrial function, and enzyme activity. However, excess iron is also cardiotoxic due to its ability to catalyze the formation of reactive oxygen species and promote oxidative damage. While mammalian cells have several redundant iron import mechanisms, they are equipped with a single iron-exporting protein, which makes the cardiovascular system particularly sensitive to iron overload. As a result, iron levels are tightly regulated at many levels to maintain homeostasis. Iron dysregulation ranges from iron deficiency to iron overload and is seen in many types of cardiovascular disease, including heart failure, myocardial infarction, anthracycline-induced cardiotoxicity, and Friedreich's ataxia. Recently, the use of intravenous iron therapy has been advocated in patients with heart failure and certain criteria for iron deficiency. Here, we provide an overview of systemic and cellular iron homeostasis in the context of cardiovascular physiology, iron deficiency, and iron overload in cardiovascular disease, current therapeutic strategies, and future perspectives.

Keywords: biology; catalysis; electrons; heart; iron; macrophages; metabolism.

Figure 1.. Systemic iron regulation.

(1) Heme iron is absorbed on the luminal side of duodenal enterocytes. Within the enterocyte, heme is broken down by HO-1 and iron can either be stored as ferritin or enter the systemic circulation through ferroportin. (2) Non-heme ferric iron is reduced to ferrous iron by DCYTB, which can then enter enterocytes through DMT1. Ferrous iron is either stored or transported into the systemic circulation via FPN1. (3) In the circulation, ferrous iron is oxidized by CP to ferric iron, after which it binds tranferrin and is shuttled through circulation to the liver and other tissues. (4) In the hepatocyte, iron enters the cell and is stored in ferritin. When systemic iron levels are high, hepatocytes upregulate expression of hepcidin, which inhibits ferroportin on macrophages and enterocytes. Abbreviations: CP, ceruloplasmin; DCYTB, duodenal cytochrome b reductase 1; DMT1, divalent metal transporter 1; FPN1, ferroportin-1; FTN, ferritin; HCP1, heme carrier protein 1; HO-1, heme oxygenase-1; Tf, transferrin. (Figure credit: Sceyence Studios)

Figure 2.. Cardiomyocyte iron homeostasis.

Transferrin-bound ferric iron enters cardiomyocytes through TFR1 and TFR2β, while non-transferrin bound ferrous iron enters through DMT1, LTCC, TTCC, and zinc transporters. The majority of cellular iron is bound by ferritin, with the remainder stored in mitochondria or existing as labile iron. Cellular iron deficiency activates the IRP-IRE system, which upregulates TFR1 and DMT1 by binding to the 3’-UTR, while downregulating FPN1, FTH, and FTL by binding to the 5’-UTR. In extreme iron deficiency, TTP binds to AREs in the 3’-UTR of certain non-essential iron-requiring mRNA transcripts to facilitate degradation and conserve iron. The only mechanism for cellular iron export is ferroportin, which is inhibited by hepcidin. Abbreviations: ACO1, aconitase 1; ARE, AU-rich element; DMT1, divalent metal transporter 1; IRE, iron responsive element; IRP, iron regulatory protein; FPN1, ferroportin-1; FTH, ferritin heavy chain; FTL, ferritin light chain; LTCC, L-type calcium channel; NDUSF1, NADH:ubiquinone oxidoreductase core subunit S1; TF, transferrin; TFR1, transferrin receptor 1; TFR2β, transferrin receptor 2β; TTCC, T-type calcium channel; TTP, tristetraprolin; UQCRFS1, ubiquinol-cytochrome c reductase, rieske iron-sulfur polypeptide 1; UTR, untranslated region; ZIP8, zinc transporter 8; ZIP14, zinc transporter 14. (Figure credit: Sceyence Studios)

Figure 3.. Overview of ferroptosis in cardiovascular disease.

Increased iron import, heme degradation, and ferritinophagy increase the labile iron pool which leads to the generation of reactive oxygen species via the Fenton reaction, ultimately promoting lipid peroxidation and ferroptosis. Abbreviations: SLC39A14, solute carrier family 39 member 13. (Figure credit: Sceyence Studios)