Testing the Iron Hypothesis in a Mouse Model of Atherosclerosis

Hepcidin, the iron-regulatory hormone and acute phase reactant, is proposed to contribute to the pathogenesis of atherosclerosis by promoting iron accumulation in plaque macrophages, leading to increased oxidative stress and inflammation in the plaque (the “iron hypothesis”). Hepcidin and iron may thus represent modifiable risk factors in atherosclerosis. We measured hepcidin expression in Apoe−/− mice with varying diets and ages. To assess the role of macrophage iron in atherosclerosis, we generated Apoe−/− mice with macrophage-specific iron accumulation by introducing the ferroportin ffe mutation. Macrophage iron loading was also enhanced by intravenous iron injection. Contrary to the iron hypothesis, we found that hepatic hepcidin expression was not increased at any stage of the atherosclerosis progression in Apoe−/− or Apoe/ffe mice and that the atherosclerotic plaque size was not increased in mice with elevated macrophage iron. Our results strongly argue against any significant role of macrophage iron in atherosclerosis progression in mice. [Display omitted] •Iron hypothesis proposes high-hepcidin, and macrophage iron promote atherosclerosis•We tested the iron hypothesis in a mouse model of atherosclerosis•Hepcidin was not increased in mice at any stage of atherosclerosis progression•Macrophage-specific iron accumulation did not worsen atherosclerosis Nemeth and colleagues now test the “iron hypothesis,” that atherosclerotic inflammation increases levels of the iron-regulatory hormone hepcidin, causing iron retention in macrophages and accelerating atherosclerosis progression. The authors instead find that hepcidin expression was unchanged during disease progression in a mouse model of atherosclerosis. Furthermore, atherosclerotic plaque size was not increased in mice with elevated iron levels in macrophages. Thus, increased hepcidin and macrophage iron may not be important contributors to atherosclerotic progression.