2. Academic Validation
  3. Heart-Specific Knockout of the Mitochondrial Thioredoxin Reductase (Txnrd2) Induces Metabolic and Contractile Dysfunction in the Aging Myocardium

Heart-Specific Knockout of the Mitochondrial Thioredoxin Reductase (Txnrd2) Induces Metabolic and Contractile Dysfunction in the Aging Myocardium

  • J Am Heart Assoc. 2015 Jul 21;4(7):e002153. doi: 10.1161/JAHA.115.002153.
Claudia Kiermayer 1,  Emily Northrup 1,  Anja Schrewe 2,  Axel Walch 3,  Martin Hrabe de Angelis 4,  Frank Schoensiegel 5,  Hans Zischka 6,  Cornelia Prehn 7,  Jerzy Adamski 8,  Raffi Bekeredjian 5,  Boris Ivandic 5,  Christian Kupatt 9,  Markus Brielmeier 1
Affiliations

Affiliations

  • 1 Research Unit Comparative Medicine, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany (C.Kiermayer, E.N., M.B.).
  • 2 Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany (A.S., M.H.A.).
  • 3 Reserach Unit Analytical Pathology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany (A.W.).
  • 4 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.).
  • 5 Department of Internal Medicine III, University of Heidelberg, Heidelberg, Germany (F.S., R.B., B.I.).
  • 6 Institute of molecular Toxicology and Pharmacology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany (H.Z.).
  • 7 Institute of Experimental Genetics, Genome Analysis Center, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany (C.P., J.A.).
  • 8 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.).
  • 9 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.).
PMID: 26199228 DOI: 10.1161/JAHA.115.002153
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.

Methods and 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.

Keywords

aging; heart failure; thioredoxin reductase 2.

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