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.

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 (Trxfl/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-CreERT2(Tam)) survived with significant decrease in nitric oxide (NO) production due to dysfunction of nitric oxide synthase (eNOS). In rescue experiments, Trxfl/fl;αMHC-Cre(Tam) or Trx;fl/fl;VECad-CreERT2(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.