The role of hepcidin and iron homeostasis in atherosclerosis

Abstract

Atherosclerotic cardiovascular disease is a major burden on global health and a leading cause of death worldwide. The pathophysiology of this chronic disease is complex, involving inflammation, lipoprotein oxidation and accumulation, plaque formation, and calcification. In 1981, Dr. Jerome Sullivan formulated the 'Iron Hypothesis', suggesting that higher levels of stored iron promote cardiovascular diseases, whereas iron deficiency may have an atheroprotective effect. This hypothesis has stimulated research focused on clarifying the role of iron in the development of atherosclerosis. However, preclinical and clinical studies have produced contradictory results and the observation that patients with hemochromatosis do not appear to have an increased risk of atherosclerosis seemed incongruous with Sullivan's initial hypothesis. The 'paradox' of systemic iron overload not being accompanied by an increased risk for atherosclerosis led to a refinement of the iron hypothesis focusing on intracellular macrophage iron. More recent in vitro and animal studies have elucidated the complex signaling pathways regulating iron, with a particular focus on hepcidin, the master regulator of body iron homeostasis. Bone morphogenetic protein (BMP) signaling is the major pathway that is required for induction of hepcidin expression in response to increasing levels of iron. Strong links between iron homeostasis, BMP signaling, inflammation and atherosclerosis have been established in both mechanistic and human studies. This review summarizes the current understanding of the role of iron homeostasis and hepcidin in the development of atherosclerosis and discusses the BMP-hepcidin-ferroportin axis as a novel therapeutic target for the treatment of cardiovascular disease.

Keywords: Atherosclerosis; Bone morphogenetic proteins; Hepcidin; Inflammation; Iron; Macrophages.

Figure 1.. Overview of the regulation of iron homeostasis.

The hepatic hormone hepcidin is the central regulator of systemic iron homeostasis. The expression of the gene encoding hepcidin (hepcidin antimicrobial protein, “HAMP”) is regulated at the transcriptional level by iron via the BMP/Smad signaling pathway, by inflammatory cytokines such as IL-6 and by IL-1β via the JAK/STAT3 pathway, and by erythropoietic demand. While iron and inflammation increase the expression of hepcidin, erythropoietic demand and iron deficiency cause suppression of hepcidin. Hepcidin regulate, the level of the sole known iron exporter, ferroportin, at the cell surface of enterocytes, hepatocytes, erythrocytes and macrophages, and thereby controls the amount of iron in the circulation. IL-6, Interleukin-6; BMP, Bone morphogenetic protein; Smad, mothers against decapentaplegic; JAK/STAT3, Janus kinase/Signal Transducer and Activator of Transcription 3.

Figure 2.. Schematic representation of the role of hepcidin in foam cell formation and the pathogenesis of atherosclerosis.

Hepcidin gene expression in the liver is induced by inflammatory cytokines IL-6 and IL1b. Hepcidin binds to ferroportin, the only-known exporter of iron, and induces the degradation of ferroportin. Iron export from macrophages is therefore reduced, and high intracellular iron levels induce a pro-inflammatory, pro-atherogenic M1 macrophage phenotype. As a result of increased intracellular iron, the production of inflammatory cytokines, including IL-6 and TNFα, is increased. High levels of reactive oxygen species (ROS) are generated, which inhibit LXRα-induced expression of the gene encoding the ABCA-1 cholesterol transporter. As a consequence, cholesterol efflux is decreased, and lipids accumulate in the cell, leading to foam cell formation within the vascular plaque. Vascular plaques increase in size, causing lumen narrowing. The dotted grey arrow indicates reduced export. Fe²⁺, ferrous iron; TNFα, Tumor necrosis factor α; IL-6, Interleukin-6; ROS, Reactive oxygen species; LXRα, Liver X receptor α; ABCA-1, ATP-binding cassette transporter 1; oxLDL, Oxidized low-density lipoprotein.