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Kiermayer, C. ; Northrup, E. ; Schrewe, A. ; Walch, A.K. ; Hrabě de Angelis, M. ; Schoensiegel, F.* ; Zischka, H. ; Prehn, C. ; Adamski, J. ; Bekeredjian, R.* ; Ivandic, B.* ; Kupatt, C.* ; Brielmeier, M.

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)
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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, Pages: , Article Number: e002153 Supplement: ,
Publisher Wiley
Reviewing status Peer reviewed