Expression of the peptide hormone hepcidin increases in cardiomyocytes under myocarditis and myocardial infarction☆

Abstract 

The micronutrient iron is an essential component that plays a role in many crucial metabolic reactions. The peptide hormone hepcidin is thought to play a central role in iron homeostasis and its expression is induced by iron overloading and inflammation. Recently, hepcidin has been reported to be expressed also in the heart; however, the kinetics of altered hepcidin expression in diseases of the heart remain unknown. In this study, we examined cardiac expression of hepcidin in rat experimental autoimmune myocarditis (EAM), human myocarditis and rat acute myocardial infarction (AMI). In rat EAM and AMI hearts, hepcidin was expressed in cardiomyocytes; ferroportin, which is a cellular iron exporter bound by hepcidin, was also expressed in various cells. Analysis of the time course of the hepcidin to cytochrome oxidase subunit 6a (Cox6a)2 expression ratio showed that it abruptly increased more than 100-fold in hearts in the very early phase of EAM and in infarcted areas 1 day after MI. The hepcidin/Cox6a2 expression ratio correlated significantly with that of interleukin-6/γ-actin in both EAM and AMI hearts (r=0.781, P<.0001 and r=0.563, P=.0003). In human hearts with histological myocarditis, the ratio was significantly higher than in those without myocarditis (0.0400±0.0195 versus 0.0032±0.0017, P=.0045). Hepcidin is strongly induced in cardiomyocytes under myocarditis and MI, conditions in which inflammatory cytokine levels increase and may play an important role in iron homeostasis and free radical generation.

Abbreviations: AMI, acute myocardial infarction, Cox6a, cytochrome oxidase subunit 6a, EAM, experimental autoimmune myocarditis, ferritin-H, ferritin heavy chain, ferritin-L, ferritin light chain, NC, non-cardiomyocytic, NCNI, non-cardiomyocytic non-inflammatory

Keywords: Hepcidin, Myocarditis, Myocardial infarction, Iron homeostatis, Reactive oxygen species, Cytokine