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Heart-specific knockout of the mitochondrial Thioredoxin reductase (Txnrd2) induces metabolic and contractile dysfunction in the aging myocardium.
J. Am. Heart Assoc. 4:e002153 (2015)
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.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Aging ; Heart Failure ; Thioredoxin Reductase 2
e-ISSN
2047-9980
Quellenangaben
Volume: 4,
Issue: 7,
Article Number: e002153
Publisher
Wiley
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
CF Comparative Medicine (CF-Comparative Medicine)
Institute of Experimental Genetics (IEG)
Institute of Pathology (PATH)
Research Unit Analytical Pathology (AAP)
Institute of Molecular Toxicology and Pharmacology (TOXI)
Molekulare Endokrinologie und Metabolismus (MEM)
Institute of Experimental Genetics (IEG)
Institute of Pathology (PATH)
Research Unit Analytical Pathology (AAP)
Institute of Molecular Toxicology and Pharmacology (TOXI)
Molekulare Endokrinologie und Metabolismus (MEM)