Thioredoxin and ventricular remodeling

Abstract

Increasing bodies of evidence indicate that reactive oxygen species (ROS) produced by mitochondria and other sources play an essential role in mediating ventricular remodeling after myocardial infarction and the development of heart failure. Antioxidants scavenge ROS, thereby maintaining the reduced environment of cells and inhibiting ventricular remodeling in the heart. Thioredoxin not only functions as a major antioxidant in the heart but also interacts with important signaling molecules and transcription factors, thereby modulating various cellular functions. The activity of thioredoxin is regulated by a variety of mechanisms, such as transcription, localization, protein-protein interaction, and post-translational modification. In this review, we will summarize the cardiac effects of thioredoxin and the mechanisms by which thioredoxin mediates inhibition of ventricular remodeling.

Figure 1. Anti-hypertrophic and anti-apoptotic effects of Trx1

Trx1 is normally localized in the cytosol, but translocates to the nucleus under stress conditions through direct interaction with importin (imp) or TXNIP. In the nucleus, Trx1 regulates the activity of various transcriptional factors. In the cytosol, Trx1 exerts anti-hypertrophic and anti-apoptotic effects by interacting with important signaling molecules, such as ASK-1, Ras, PTEN/Akt, and NFκB. Trx1 is also secreted to the extracellular space under stress conditions, thereby protecting neighboring cells.

Figure 2. Post-translational modifications of Trx1

Trx1 has five modifiable cysteines (closed circles). Two of them, namely Cys-32 and Cys-35, in the catalytic site are involved in the enzymatic activity of Trx1. Under oxidative stresses, Trx1 forms disulfide bonds (S-S) between Cys-32 and Cys-35 and/or between Cys-62 and Cys-69, or a mixed disulfide bond with glutathione, called glutathionylation (S-SG). The activity of Trx1 or the accessibility of TrxR1 to Trx1 is inhibited by these oxidative modifications. On the other hand, Trx1 can be modified by NO and peroxynitrite. Trx1 is nitrosylated at Cys-69 (S-NO), which leads to the enhanced activity of Trx1. Trx1 has Tyr-49, which is nitrated by peroxynitrite. Nitration of Tyr-49 irreversibly suppresses the activity of Trx1.