Key result
Heart-specific inactivation of Txnrd2 in adult mice led to increased left ventricular end-systolic diameters, decreased fractional shortening and ejection fraction, and mitochondrial degeneration.
Heart-specific knockout of Txnrd2 in adult mice leads to metabolic and contractile dysfunction during aging, suggesting Txnrd2 is crucial for sustaining heart function and may modify heart failure.
Does not support clinical translation; leaves open Txnrd2 as a modifier of age-related cardiomyopathy.
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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Kiermayer et al. (2015) studied Aging myocardium. Heart-specific Txnrd2 inactivation vs. Controls was evaluated on Morphological and functional analysis of hearts and isolated mitochondria. Heart-specific inactivation of Txnrd2 in adult mice led to increased left ventricular end-systolic diameters, decreased fractional shortening and ejection fraction, and mitochondrial degeneration.
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