Cardiomyocyte-specific deletion of thioredoxin promotes myocardial injury, infarction and mitochondrial dysfunction: translocation of cytosolic thioredoxin into mitochondria rescue myocardial dysfunction by restoration of cardiac mitochondrial structure and function

Q: What are the key findings of this study?

Cardiomyocyte-specific Trx deletion caused 60% mortality within 14 days and ~50% lower mitochondrial respiration, which was rescued by recombinant human Trx.

Q: What is the clinical evidence from this study?

Population: Myocardial injury, infarction, and mitochondrial dysfunction induced by conditional deletion of cytosolic thioredoxin (Trx). Intervention: Cardiomyocyte- or endothelial-specific Trx deletion and rescue with recombinant human thioredoxin (rhTrx) vs. Tamoxifen-untreated control mice (injected with sunflower oil vehicle) or Trx-deleted mice without rhTrx treatment. Primary outcome: 14-day mortality and myocardial/mitochondrial dysfunction (p=<0.05).

Q: What does this research mean for the field?

Cardiomyocyte-specific deletion of cytosolic thioredoxin causes severe myocardial injury, infarction, substantial mortality, and impaired mitochondrial respiration, which can be rescued by recombinant human thioredoxin. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

Q: What question did this study set out to answer?

To determine the cell-specific roles of cytosolic thioredoxin in cardiomyocytes and endothelial cells and assess whether recombinant thioredoxin can rescue cardiac pathology.

Sudhir Kumar; Richa Rani; Venkatesh Kundumani‐Sridharan; Scott Shurmur; Kumuda C. Das

doi:10.1016/j.redox.2026.104435

October 10, 2026Redox BiologyOpen Access

Cardiomyocyte-specific deletion of thioredoxin promotes myocardial injury, infarction and mitochondrial dysfunction: translocation of cytosolic thioredoxin into mitochondria rescue myocardial dysfunction by restoration of cardiac mitochondrial structure and function

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Key result

Cardiomyocyte Trx deletion causes ~60% 14-day mortality, fully reversed by recombinant human Trx.

P<0.05

Figures

Why the study?

Cytosolic thioredoxin (Trx) is involved in cellular redox functions, but its specific role in cardiomyocytes or endothelial cells in the normal heart remained unclear.

Does conditional deletion of cytosolic thioredoxin in cardiomyocytes or endothelial cells impair myocardial and mitochondrial function in adult mice, and can exogenous recombinant human thioredoxin rescue these defects?

Key Points

To determine the cell-specific roles of cytosolic thioredoxin in cardiomyocytes and endothelial cells and assess whether recombinant thioredoxin can rescue cardiac pathology.
Generated tamoxifen-inducible knockout mouse strains with specific deletion of Trx in cardiomyocytes (Trx fl/fl;αMHC-Cre) or endothelial cells (Trx fl/fl;VECad-CreERT2).
Assessed cardiac structure and performance using echocardiography, histology, serum cardiac troponin-I, transmission electron microscopy, and mitochondrial oxygen consumption rates.
Administered human recombinant thioredoxin (rhTrx) to test whether it could rescue mitochondrial defects, gene expression, and myocardial performance.
Cardiomyocyte-specific Trx deletion led to severe myocardial infarction, marked troponin release, CD45+ leukocyte infiltration, and significant mortality within 3 weeks.
Loss of myocyte Trx significantly reduced ejection fraction and fractional shortening while causing roughly a 50% decrease in mitochondrial oxygen consumption rate alongside loss of complex I (ND2, ND3, ND4) and complex III (mt-Cyt.B) proteins.
Endothelial Trx knockout impaired eNOS and nitric oxide production without inducing mortality, whereas recombinant thioredoxin administration rescued mitochondrial structure, Ogg1 activity, and heart function in both models.

Structured PICO

Does conditional deletion of cytosolic thioredoxin in cardiomyocytes or endothelial cells impair myocardial and mitochondrial function in adult mice, and can exogenous recombinant human thioredoxin rescue these defects?

P

Population

Preclinical study in 8- to 12-week-old male and female mice with tamoxifen-induced cardiomyocyte- or endothelial-specific deletion of cytosolic thioredoxin (Trx), followed for up to 14 days.

I

Intervention

Tamoxifen-induced conditional deletion of cytosolic Trx (75 mg/kg intraperitoneally in sunflower oil for 5 days), followed in rescue experiments by intravenous (tail-vein) administration of recombinant human thioredoxin (rhTrx, 5 mg/kg in saline for 3 to 4 consecutive days).

C

Comparator

Control Trx fl/fl;αMHC-Cre and Trx fl/fl;VECad-CreERT2 mice injected intraperitoneally with sunflower oil vehicle without tamoxifen, or tamoxifen-treated conditional knockout mice without rhTrx rescue.

O

Outcome

Mouse survival (mortality over 14 days), myocardial function (ejection fraction, fractional shortening, cardiac output, isovolumetric relaxation time, myocardial performance index via echocardiography), myocardial infarction/ischemia (TTC staining, serum cardiac troponin-I), and cardiac mitochondrial structure and function (TEM morphometry and oxygen consumption rate).surrogate

Main Result

Absolute Event Rate: 60% vs 0%

p-value: p=<0.05

This preclinical study demonstrates that cytosolic thioredoxin is essential for maintaining cardiac mitochondrial bioenergetics, DNA repair (Ogg1), and endothelial eNOS/NO signaling, and that exogenous recombinant human Trx can translocate into cardiac mitochondria to rescue severe myocardial dysfunction.

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Implication

Recombinant thioredoxin rescues mitochondrial dysfunction after cardiomyocyte Trx deletion in mice; leaves open therapeutic translation to human cardiac disease.

Abstract

Cytosolic thioredoxin is a protein disulfide reductase that is involved in several redox-related functions within cells. However, the specific role of Trx in cardiomyocytes or endothelial cells in the normal heart remains unclear. We created a Trx-floxed mouse strain (Trx fl/fl ) to specifically understand whether deletion of Trx in cardiomyocytes or endothelial cell would have specific detrimental myocardial effects. We show that specific deletion of Trx in cardiomyocytes of adult mice ( Trx fl/fl ;αMHC-Cre (Tam ) ) caused severe ischemia and infarction along with heart mitochondrial dysfunction and significant mortality within 3 weeks. In contrast, mice with deletion of Trx in the endothelial cells ( Trx; fl/fl ;VECad-CreER T2(Tam) ) survived with significant decrease in nitric oxide (NO) production due to dysfunction of nitric oxide synthase (eNOS). In rescue experiments, Trx fl/fl ;αMHC-Cre (Tam) or Trx; fl/fl ;VECad-CreER T2(Tam) mice treated with human recombinant thioredoxin (rhTrx) rescued altered mitochondrial structure and function with improved heart function. Further, rhTrx restored the expression of mitochondrial genes and proteins and Ogg1 activity. Taken together, our study demonstrates a critical role of Trx within the cardiac mitochondria and endothelial cells that rescue myocardial dysfunction due to deletion of Trx in cardiomyocytes as well as endothelial cell by rescue of mitochondrial structure, function, and improving eNOS function within the heart.

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Cite This Study

Kumar et al. (2026) studied Myocardial injury, infarction, and mitochondrial dysfunction induced by conditional deletion of cytosolic thioredoxin (Trx). Cardiomyocyte- or endothelial-specific Trx deletion and rescue with recombinant human thioredoxin (rhTrx) vs. Tamoxifen-untreated control mice (injected with sunflower oil vehicle) or Trx-deleted mice without rhTrx treatment was evaluated on 14-day mortality and myocardial/mitochondrial dysfunction (p=<0.05). Cardiomyocyte-specific Trx deletion caused 60% mortality within 14 days and ~50% lower mitochondrial respiration, which was rescued by recombinant human Trx.

synapsesocial.com/papers/6aee6b6871a7594806220905 https://doi.org/10.1016/j.redox.2026.104435

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Cardiomyocyte-specific deletion of thioredoxin promotes myocardial injury, infarction and mitochondrial dysfunction: translocation of cytosolic thioredoxin into mitochondria rescue myocardial dysfunction by restoration of cardiac mitochondrial structure and function

Figures

Key Points

Structured PICO

Main Result

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Implication

Abstract

Discussion

Cite This Study

Cardiomyocyte-specific deletion of thioredoxin promotes myocardial injury, infarction and mitochondrial dysfunction: translocation of cytosolic thioredoxin into mitochondria rescue myocardial dysfunction by restoration of cardiac mitochondrial structure and function

Figures

Key Points

Structured PICO

Main Result

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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