title: Iron-regulatory proteins secure iron availability in cardiomyocytes to prevent heart failure.
abstract: Iron deficiency (ID) is associated with adverse outcomes in heart failure (HF) but the underlying mechanisms are incompletely understood. Intracellular iron availability is secured by two mRNA-binding iron-regulatory proteins (IRPs), IRP1 and IRP2. We generated mice with a cardiomyocyte-targeted deletion of Irp1 and Irp2 to explore the functional implications of ID in the heart independent of systemic ID and anaemia.
  
  
  
  Iron content in cardiomyocytes was reduced in Irp-targeted mice. The animals were not anaemic and did not show a phenotype under baseline conditions. Irp-targeted mice, however, were unable to increase left ventricular (LV) systolic function in response to an acute dobutamine challenge. After myocardial infarction, Irp-targeted mice developed more severe LV dysfunction with increased HF mortality. Mechanistically, the activity of the iron-sulphur cluster-containing complex I of the mitochondrial electron transport chain was reduced in left ventricles from Irp-targeted mice. As demonstrated by extracellular flux analysis in vitro, mitochondrial respiration was preserved at baseline but failed to increase in response to dobutamine in Irp-targeted cardiomyocytes. As shown by 31P-magnetic resonance spectroscopy in vivo, LV phosphocreatine/ATP ratio declined during dobutamine stress in Irp-targeted mice but remained stable in control mice. Intravenous injection of ferric carboxymaltose replenished cardiac iron stores, restored mitochondrial respiratory capacity and inotropic reserve, and attenuated adverse remodelling after myocardial infarction in Irp-targeted mice but not in control mice. As shown by electrophoretic mobility shift assays, IRP activity was significantly reduced in LV tissue samples from patients with advanced HF and reduced LV tissue iron content.
  
  
  
  ID in cardiomyocytes impairs mitochondrial respiration and adaptation to acute and chronic increases in workload. Iron supplementation restores cardiac energy reserve and function in iron-deficient hearts.
authors.affiliation: Division of Molecular and Translational Cardiology, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany.|Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany.
authors.forename: Saba
authors.initials: S
authors.lastname: Haddad
authors.affiliation: Division of Molecular and Translational Cardiology, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany.|Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany.
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: European Molecular Biology Laboratory, Meyerhofstraße 1, 69117 Heidelberg, Germany.|Division of Virus-associated Carcinogenesis, German Cancer Research Centre, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: Bruno
authors.initials: B
authors.lastname: Galy
authors.affiliation: Division of Molecular and Translational Cardiology, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany.|Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany.
authors.forename: Mortimer
authors.initials: M
authors.lastname: Korf-Klingebiel
authors.affiliation: Division of Molecular and Translational Cardiology, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany.|Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany.
authors.forename: Valentin
authors.initials: V
authors.lastname: Hirsch
authors.affiliation: Division of Molecular and Translational Cardiology, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany.|Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany.
authors.forename: Abdul M
authors.initials: AM
authors.lastname: Baru
authors.affiliation: Division of Molecular and Translational Cardiology, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany.|Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany.
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Rostami
authors.affiliation: Division of Molecular and Translational Cardiology, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany.|Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany.
authors.forename: Marc R
authors.initials: MR
authors.lastname: Reboll
authors.affiliation: Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Heineke
authors.affiliation: Department of Molecular Cardiology, University of Düsseldorf, Universitätsstraße 1, 40225 Düsseldorf, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Flögel
authors.affiliation: Institute of Cell Biology, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Groos
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, University of Bochum, Georgstraße 11, 32545 Bad Oeynhausen, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Renner
authors.affiliation: Department of Cardiology and Pneumology, University of Göttingen, Robert-Koch-Straße 40, 37075 Göttingen, Germany.
authors.forename: Karl
authors.initials: K
authors.lastname: Toischer
authors.affiliation: Department of Analytical Chemistry, Leibniz University Hannover, Callinstraße 1, 30167 Hannover, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Zimmermann
authors.affiliation: Institute of Clinical Pharmacology, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Engeli
authors.affiliation: Institute of Clinical Pharmacology, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Jordan
authors.affiliation: Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany.
authors.forename: Johann
authors.initials: J
authors.lastname: Bauersachs
authors.affiliation: European Molecular Biology Laboratory, Meyerhofstraße 1, 69117 Heidelberg, Germany.
authors.forename: Matthias W
authors.initials: MW
authors.lastname: Hentze
authors.affiliation: Division of Molecular and Translational Cardiology, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany.|Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany.
authors.forename: Kai C
authors.initials: KC
authors.lastname: Wollert
authors.affiliation: Division of Molecular and Translational Cardiology, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany.|Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany.
authors.forename: Tibor
authors.initials: T
authors.lastname: Kempf
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology; D004298:Dopamine / Q000494:pharmacology; D005290:Ferric Compounds / Q000494:pharmacology; D005293:Ferritins / Q000378:metabolism; D006333:Heart Failure / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D006801:Humans; D007501:Iron / Q000378:metabolism; D000090463:Iron Deficiencies; D035925:Iron-Regulatory Proteins / Q000172:deficiency / Q000502:physiology*; D018810:Magnetic Resonance Angiography; D008320:Maltose / Q000031:analogs & derivatives / Q000494:pharmacology; D008929:Mitochondria, Heart / Q000502:physiology; D032383:Myocytes, Cardiac / Q000378:metabolism*; D010641:Phenotype; D012333:RNA, Messenger / Q000502:physiology; D016277:Ventricular Function, Left / Q000502:physiology
chemical_list: D002316:Cardiotonic Agents; D005290:Ferric Compounds; D035925:Iron-Regulatory Proteins; D012333:RNA, Messenger; C522335:ferric carboxymaltose; D008320:Maltose; D005293:Ferritins; D007501:Iron; D004298:Dopamine
keywords: 31P-Magnetic resonance spectroscopy; Energy metabolism; Extracellular flux analysis; Heart failure; Iron deficiency