title: Heart-Specific Knockout of the Mitochondrial Thioredoxin Reductase (Txnrd2) Induces Metabolic and Contractile Dysfunction in the Aging Myocardium.
abstract: BACKGROUND
  Ubiquitous deletion of thioredoxin reductase 2 (Txnrd2) in mice is embryonically lethal and associated with abnormal heart development, while constitutive, heart-specific Txnrd2 inactivation leads to dilated cardiomyopathy and perinatal death. The significance of Txnrd2 in aging cardiomyocytes, however, has not yet been examined.
  
  
  RESULTS
  The tamoxifen-inducible heart-specific αMHC-MerCreMer transgene was used to inactivate loxP-flanked Txnrd2 alleles in adult mice. Hearts and isolated mitochondria from aged knockout mice were morphologically and functionally analyzed. Echocardiography revealed a significant increase in left ventricular end-systolic diameters in knockouts. Fractional shortening and ejection fraction were decreased compared with controls. Ultrastructural analysis of cardiomyocytes of aged mice showed mitochondrial degeneration and accumulation of autophagic bodies. A dysregulated autophagic activity was supported by higher levels of lysosome-associated membrane protein 1 (LAMP1), microtubule-associated protein 1A/1B-light chain 3-I (LC3-I), and p62 in knockout hearts. Isolated Txnrd2-deficient mitochondria used less oxygen and tended to produce more reactive oxygen species. Chronic hypoxia inducible factor 1, α subunit stabilization and altered transcriptional and metabolic signatures indicated that energy metabolism is deregulated.
  
  
  CONCLUSIONS
  These results imply a novel role of Txnrd2 in sustaining heart function during aging and suggest that Txnrd2 may be a modifier of heart failure.
authors.affiliation: Research Unit Comparative Medicine, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany (C.Kiermayer, E.N., M.B.).
authors.forename: Claudia
authors.initials: C
authors.lastname: Kiermayer
authors.affiliation: Research Unit Comparative Medicine, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany (C.Kiermayer, E.N., M.B.).
authors.forename: Emily
authors.initials: E
authors.lastname: Northrup
authors.affiliation: Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany (A.S., M.H.A.).
authors.forename: Anja
authors.initials: A
authors.lastname: Schrewe
authors.affiliation: Reserach Unit Analytical Pathology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany (A.W.).
authors.forename: Axel
authors.initials: A
authors.lastname: Walch
authors.affiliation: Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany (A.S., M.H.A.) Chair of Experimental Genetics, Technische Universität München, Munich, Germany (M.H.A., J.A.).
authors.forename: Martin Hrabe
authors.initials: MH
authors.lastname: de Angelis
authors.affiliation: Department of Internal Medicine III, University of Heidelberg, Heidelberg, Germany (F.S., R.B., B.I.).
authors.forename: Frank
authors.initials: F
authors.lastname: Schoensiegel
authors.affiliation: Institute of molecular Toxicology and Pharmacology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany (H.Z.).
authors.forename: Hans
authors.initials: H
authors.lastname: Zischka
authors.affiliation: Institute of Experimental Genetics, Genome Analysis Center, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany (C.P., J.A.).
authors.forename: Cornelia
authors.initials: C
authors.lastname: Prehn
authors.affiliation: Institute of Experimental Genetics, Genome Analysis Center, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany (C.P., J.A.) Chair of Experimental Genetics, Technische Universität München, Munich, Germany (M.H.A., J.A.).
authors.forename: Jerzy
authors.initials: J
authors.lastname: Adamski
authors.affiliation: Department of Internal Medicine III, University of Heidelberg, Heidelberg, Germany (F.S., R.B., B.I.).
authors.forename: Raffi
authors.initials: R
authors.lastname: Bekeredjian
authors.affiliation: Department of Internal Medicine III, University of Heidelberg, Heidelberg, Germany (F.S., R.B., B.I.).
authors.forename: Boris
authors.initials: B
authors.lastname: Ivandic
authors.affiliation: I. Medizinische Klinik und Poliklinik, Klinikum Rechts der Isar, TU Munich, Munich, Germany (C.K.) German Center for Cardiovascular Research (DZHK) partner site Munich Heart Alliance, Munich, Germany (C.K.).
authors.forename: Christian
authors.initials: C
authors.lastname: Kupatt
authors.affiliation: Research Unit Comparative Medicine, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany (C.Kiermayer, E.N., M.B.).
authors.forename: Markus
authors.initials: M
authors.lastname: Brielmeier
mesh_terms: D000367:Age Factors; D000818:Animals; D001343:Autophagy; D001794:Blood Pressure; D004195:Disease Models, Animal; D004734:Energy Metabolism; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006333:Heart Failure / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D051907:Lysosomal Membrane Proteins / Q000235:genetics / Q000378:metabolism; D055432:Metabolomics / Q000379:methods; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D008929:Mitochondria, Heart / Q000201:enzymology / Q000648:ultrastructure; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000201:enzymology* / Q000648:ultrastructure; D018384:Oxidative Stress; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013318:Stroke Volume; D054482:Thioredoxin Reductase 2 / Q000172:deficiency* / Q000235:genetics; D013997:Time Factors; D018487:Ventricular Dysfunction, Left / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D016277:Ventricular Function, Left; D052118:Lysosomal-Associated Membrane Protein 1
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051907:Lysosomal Membrane Proteins; D008869:Microtubule-Associated Proteins; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D054482:Thioredoxin Reductase 2; C497443:Hif1a protein, mouse; C052255:Lamp1 protein, mouse; D052118:Lysosomal-Associated Membrane Protein 1; C480860:Map1lc3b protein, mouse; C516128:Txnrd2 protein, mouse
keywords: aging; heart failure; thioredoxin reductase 2