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

Abstract

BackgroundUbiquitous 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 ResultsThe 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.ConclusionsThese results imply a novel role of Txnrd2 in sustaining heart function during aging and suggest that Txnrd2 may be a modifier of heart failure.

Extracellular Vesicles Derived from Induced Pluripotent Stem Cells Promote Renoprotection in Acute Kidney Injury Model

“…Txn1 is a cytoplasmic enzyme and has been described to protect the kidney from oxidative stress, and overexpression of Txn1 resulted in the attenuation of the damage by IRI [44,45]. Txnrd2 is known to be an H 2 O 2 scavenger and is responsible for maintaining the redox homeostasis by eliminating H 2 O 2 and preserving mitochondria integrity [46]. In addition, Gstk1 is also another anti-ROS enzyme-modulated gene by iPSC-EV administration that is present in the mitochondria and possesses glutathione-conjugating activity towards halogenated aromatics [47,48] and, therefore, contributes to the reduction of the renal damage given by IRI.…”

Analysis of Selenoprotein Expression in Response to Dietary Selenium Deficiency During Pregnancy Indicates Tissue Specific Differential Expression in Mothers and Sex Specific Changes in the Fetus and Offspring

“…al. showed, in a knockout model of Txnrd2, myocardium contractile and metabolic function was induced, suggesting Txnrd2 may be a modifier of heart failure during aging [33]. Conversely, at E18.5, expression of both Txnrd1 and Txnrd2 was significantly increased in all tissues.…”

Population Structure, and Selection Signatures Underlying High-Altitude Adaptation Inferred From Genome-Wide Copy Number Variations in Chinese Indigenous Cattle

“…TXNRD2 encodes the mitochondrial thioredoxin reductase 2 (TXNRD2). Heartspecific TXNRD2-deficient mice showed reduced blood pressure, and stabilization of HIF-1a (Kiermayer et al, 2015). Additionally, overexpression of TXNRD2 attenuated NOevoked accumulation and transactivation of HIF-1a in HEK293 cells (Zhou et al, 2008).…”