title: Cardiac ferroportin regulates cellular iron homeostasis and is important for cardiac function.
abstract: Iron is essential to the cell. Both iron deficiency and overload impinge negatively on cardiac health. Thus, effective iron homeostasis is important for cardiac function. Ferroportin (FPN), the only known mammalian iron-exporting protein, plays an essential role in iron homeostasis at the systemic level. It increases systemic iron availability by releasing iron from the cells of the duodenum, spleen, and liver, the sites of iron absorption, recycling, and storage respectively. However, FPN is also found in tissues with no known role in systemic iron handling, such as the heart, where its function remains unknown. To explore this function, we generated mice with a cardiomyocyte-specific deletion of Fpn. We show that these animals have severely impaired cardiac function, with a median survival of 22 wk, despite otherwise unaltered systemic iron status. We then compared their phenotype with that of ubiquitous hepcidin knockouts, a recognized model of the iron-loading disease hemochromatosis. The phenotype of the hepcidin knockouts was far milder, with normal survival up to 12 mo, despite far greater iron loading in the hearts. Histological examination demonstrated that, although cardiac iron accumulates within the cardiomyocytes of Fpn knockouts, it accumulates predominantly in other cell types in the hepcidin knockouts. We conclude, first, that cardiomyocyte FPN is essential for intracellular iron homeostasis and, second, that the site of deposition of iron within the heart determines the severity with which it affects cardiac function. Both findings have significant implications for the assessment and treatment of cardiac complications of iron dysregulation.
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, United Kingdom; samira.lakhal-littleton@dpag.ox.ac.uk.
authors.forename: Samira
authors.initials: S
authors.lastname: Lakhal-Littleton
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, United Kingdom;
authors.forename: Magda
authors.initials: M
authors.lastname: Wolna
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, United Kingdom;
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: Carr
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, United Kingdom;
authors.forename: Jack J J
authors.initials: JJ
authors.lastname: Miller
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, United Kingdom;
authors.forename: Helen C
authors.initials: HC
authors.lastname: Christian
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, United Kingdom;
authors.forename: Vicky
authors.initials: V
authors.lastname: Ball
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BH, United Kingdom;
authors.forename: Ana
authors.initials: A
authors.lastname: Santos
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BH, United Kingdom;
authors.forename: Rebeca
authors.initials: R
authors.lastname: Diaz
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BH, United Kingdom;
authors.forename: Daniel
authors.initials: D
authors.lastname: Biggs
authors.affiliation: Dunn School of Pathology, University of Oxford, Oxford OX1 3RF, United Kingdom; and.
authors.forename: Richard
authors.initials: R
authors.lastname: Stillion
authors.affiliation: Department of Earth Sciences, University of Oxford, Oxford OX1 3AN, United Kingdom.
authors.forename: Philip
authors.initials: P
authors.lastname: Holdship
authors.affiliation: Department of Earth Sciences, University of Oxford, Oxford OX1 3AN, United Kingdom.
authors.forename: Fiona
authors.identifier: http://orcid.org/0000-0001-6277-4851
authors.initials: F
authors.lastname: Larner
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, United Kingdom;
authors.forename: Damian J
authors.identifier: http://orcid.org/0000-0002-0780-8905
authors.initials: DJ
authors.lastname: Tyler
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, United Kingdom;
authors.forename: Kieran
authors.initials: K
authors.lastname: Clarke
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BH, United Kingdom;
authors.forename: Benjamin
authors.initials: B
authors.lastname: Davies
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, United Kingdom;
authors.forename: Peter A
authors.initials: PA
authors.lastname: Robbins
mesh_terms: D000818:Animals; D027682:Cation Transport Proteins / Q000502:physiology*; D006321:Heart / Q000502:physiology*; D006706:Homeostasis; D007501:Iron / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000098742:Ferroportin
chemical_list: D027682:Cation Transport Proteins; D000098742:Ferroportin; D007501:Iron
keywords: cardiomyocyte; ferroportin; heart; hepcidin; iron