ArticleCirculation2015
Thioredoxin-2 inhibits mitochondrial reactive oxygen species generation and apoptosis stress kinase-1 activity to maintain cardiac function.
Article in Circulation, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 110 papers.
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Who cites it
110 citing papers in PubMed, 166 citations in OpenAlex.
- Organelle network dysfunction in primary cardiomyopathy: An integrated perspective on pathogenesis and therapeutics.Journal of molecular and cellular cardiology plus · 2026Review
- Crosstalk of thioredoxin system and programmed cell death: from pathophysiology to novel therapy.Redox biology · 2026Review
- TrxR2 Lactylation Facilitates Mitochondrial Protection and Endothelial Ferroptosis Resistance in Diabetic Cardiomyopathy.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Hypoxia, ROS, and HIF Signaling in I/R Injury: Implications and Future Prospects.Antioxidants (Basel, Switzerland) · 2026Review
- Identification of potential hub genes related to ferroptosis and hypoxia in dilated cardiomyopathy: a bioinformatic analysis with preliminary experimental validation.Experimental biology and medicine (Maywood, N.J.) · 2026Article
- Mitochondrial remodeling in heart failure with reduced ejection fraction.Frontiers in physiology · 2026Review
- Involvement of the thioredoxin system in multiple diseases: A focus on mechanisms of action in autophagy and ferroptosis (Review).Molecular medicine reports · 2026Review
- Sirtuin 1 Activation Mitigates Murine Vasculitis Severity by Promoting Autophagy and Mitophagy.bioRxiv : the preprint server for biology · 2025Article
- Effect of mitochondrial translocator protein TSPO on LPS-induced cardiac dysfunction.Journal of advanced research · 2025Article
- Enrichable cross-linkers for mapping direct protein interactions.Genome biology · 2025Article
- The bidirectional regulatory effect of TXNRD2 methylation in patients with chronic heart failure and its nonlinear dose-response relationship with key clinical parameters.Journal of cardiothoracic surgery · 2025Article
- Retinoic acid signaling and metabolism in heart failure.American journal of physiology. Heart and circulatory physiology · 2025Review
- Musculoskeletal miRNA profiling after exposure to simulated space stressors in mice.microPublication biology · 2025Article
- Formoterol promotes mitochondrial biogenesis, improves liver regeneration, and suppresses liver injury and inflammation after liver resection in mice with endotoxemia.International journal of physiology, pathophysiology and pharmacology · 2025Article
- Mouse models used to test the role of reactive oxygen species in aging and age-related chronic diseases.Free radical biology & medicine · 2024Review
- Thioredoxin System Protein Expression in Carcinomas of the Pancreas, Distal Bile Duct, and Ampulla in the United Kingdom.Diseases (Basel, Switzerland) · 2024Article
- NAD+ metabolism and therapeutic strategies in cardiovascular diseases.Atherosclerosis plus · 2024Review
- Disulfide stress and its role in cardiovascular diseases.Redox biology · 2024Review
- Histone deacetylase inhibitor, Trichostatin A mitigates ionizing radiation induced redox imbalance by regulating NRF2/GPX4/PINK1/PARKIN signaling in mice intestine.Molecular biology reports · 2024Article
- The Ubiquinone-Ubiquinol Redox Cycle and Its Clinical Consequences: An Overview.International journal of molecular sciences · 2024Review
50 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
12 authors at 3 institutions in 2 countries.
Funding
Abstract
backgroundThioredoxin 2 (Trx2) is a key mitochondrial protein that regulates cellular redox and survival by suppressing mitochondrial reactive oxygen species generation and by inhibiting apoptosis stress kinase-1 (ASK1)-dependent apoptotic signaling. To date, the role of the mitochondrial Trx2 system in heart failure pathogenesis has not been investigated. METHODS AND
resultsWestern blot and histological analysis revealed that Trx2 protein expression levels were reduced in hearts from patients with dilated cardiomyopathy, with a concomitant increase in ASK1 phosphorylation/activity. Cardiac-specific Trx2 knockout mice develop spontaneous dilated cardiomyopathy at 1 month of age with increased heart size, reduced ventricular wall thickness, and a progressive decline in left ventricular contractile function, resulting in mortality due to heart failure by ≈4 months of age. The progressive decline in cardiac function observed in cardiac-specific Trx2 knockout mice was accompanied by the disruption of mitochondrial ultrastructure, mitochondrial membrane depolarization, increased mitochondrial reactive oxygen species generation, and reduced ATP production, correlating with increased ASK1 signaling and increased cardiomyocyte apoptosis. Chronic administration of a highly selective ASK1 inhibitor improved cardiac phenotype and reduced maladaptive left ventricular remodeling with significant reductions in oxidative stress, apoptosis, fibrosis, and cardiac failure. Cellular data from Trx2-deficient cardiomyocytes demonstrated that ASK1 inhibition reduced apoptosis and reduced mitochondrial reactive oxygen species generation.
conclusionsOur data support an essential role for mitochondrial Trx2 in preserving cardiac function by suppressing mitochondrial reactive oxygen species production and ASK1-dependent apoptosis. Inhibition of ASK1 represents a promising therapeutic strategy for the treatment of dilated cardiomyopathy and heart failure.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.