Editorial Hemochromatosis Protein (HFE) Knockout Mice As a Novel Model of Hemochromatosis: Implications for Study and Management of Iron-Overload Cardiomyopathy Pavel Zhabyeyev, PhD, and Gavin Y. Oudit, MD, PhD, FRCPC Division of Cardiology, Department of Medicine, Department of Physiology, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada See article by Djemai et al., pages 904e910 of this issue. Iron plays a crucial role in a large number of physiological functions: (1) oxygen transport as a component of hemoglobin and myoglobin, (2) oxidative phosphorylation as a component of iron-sulphur, cluster-containing enzymes (cytochromes, nicotinamide adenine dinucleotide phosphate, and succinate dehydrogenases), and (3) production of reactive oxygen species (ROS) as a component of peroxide- and nitric-oxidee generating enzymes. 1,2 Iron homeostasis is carefully regulated by soluble transferrin, transferrin receptor 1 (TfR1), iron sensitivity complex, and hepcidin, which are responsible for the negative feedback loop in iron homeostasis (Fig 1A). 1,3,4 As iron is absorbed through the enterocyte, it is bound by specific iron transport proteins (transferrin) and iron storage proteins (ferritin). Increased saturation of transferrin (accumulation of iron-containing holo-transferrin) in the plasma results in disassociation of human hemochromatosis (HFE) protein from TfR1 because of binding of holo-transferrin (Fig 1A). 5 Released HFE protein becomes available to form an iron-sensing com- plex consisting of HFE protein, hemojuvelin (HJV), TfR2, bone morphogenetic protein (BMP), and BMP receptor. This complex is activated by SMAD signaling transcription of the HAMP gene, which produces hepcidin. Hepcidin acts as a negative regulator of iron uptake in the enterocyte, preventing further accumulation of iron in the body (Fig 1A). The HFE deletion (HFE e/e ) is classified as type 1 primary hemochromatosis, whereas deletion of HJV (HJV e/e ) results in type 2 primary hemochromatosis, and both these types account for the majority of cases of hereditary hemochroma- tosis (Fig 1B). HFE mutations constitute approximately 90% of hemochromatosis phenotypes in white populations of Eu- ropean descent, with C282Y being the most prevalent. 6,7 In individuals homozygous for the C282Y mutation, the risk for the development of iron-overload diseases is 28.4% for men and 1.2% for women, mainly because of the estrogen- dependent reduction in ROS production, 8 illustrating important sex-specific manifestations of iron-overload car- diomyopathy. 8,9 Polymorphisms in the transferrin, transferrin receptor 2, and bone morphogenetic protein 2 genes affect the development of the iron-overload phenotype associated with the C282Y genotype. 6 In the absence of adequate preventive measures, patients with primary hemochromatosis experience iron-overload cardiomyopathy, which is a major cause of the morbidity and mortality in these patients. 10-12 Survival with iron-overload cardiomyopathy is only 44% at 1 year and < 25% at 5 years. 13 To date, murine models of iron-overload cardiomyopathy, such as wild-type mice injected with iron dextran, or HJV e/e on iron-rich diets, reproduce many phenotypic features seen in patients with iron-overload car- diomyopathy, but not systolic dysfunction. 8,14-16 In this issue of the Canadian Journal of Cardiology, Djemai et al. 17 demonstrate that aging in the HFE knockout (HFE e/ e ) murine model of primary hemochromatosis, in which iron overload is achieved through dietary iron uptake, results in iron-overload cardiomyopathy. Similar to patients with pri- mary hemochromatosis, HFE e/e mice lack proper activity of the HFE protein, which leads to low levels of hepcidin and accumulation of iron from dietary sources. Importantly, the cardiomyopathy in the HFE mutant was associated with myocardial fibrosis, an important pathologic feature associated with iron-overload cardiomyopathy. 8,16 As a result, HFE e/e mice develop ventricular dilatation and systolic dysfunction by the age of 14 months. Moreover, in this model, heterozygous mice (HFE þ/e ) also have phenotypic features of iron-overload cardiomyopathy, including diminished systolic function, with a slower onset. By 20 months of age (equivalent to a 50-year- old human), both homozygous (HFE e/e ) and heterozygous (HFE þ/e ) mutant mice show equivalent degrees of ventricular dilatation and systolic dysfunction. In humans, heterozygotes for C282Y (equivalent of HFE þ/e mice) have an elevated transferrin saturation level and elevated hepatic iron index but are unlikely to develop iron overload in the absence of other compounding factors such as another mutation in an iron- related gene (compound heterozygote) or the presence of additional risk factors. 18-21 The increased risk of Canadian Journal of Cardiology 33 (2017) 835e837 Received for publication April 17, 2017. Accepted April 27, 2017. Corresponding author: Dr Gavin Y. Oudit, Division of Cardiology, Department of Medicine, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta T6G 2S2, Canada. Tel.: þ1-780-407-8569; fax: þ1-780-407- 6452. E-mail: gavin.oudit@ualberta.ca See page 837 for disclosure information. http://dx.doi.org/10.1016/j.cjca.2017.04.013 0828-282X/Ó 2017 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.