The thioredoxin system in ischemic heart mice

Abstract

Thioredoxin-1 (Trx-1), a 12 kDa protein, is a highly protective protein against myocardial infarction in murine model. Whether this protective phenomenon can be attributed to cardiomyocyte regeneration or survival, a consequence of the reduced levels of cellular ROS, inflammatory cytokines and/or protein oxidation, or to another phenomenon is not known. Thus, Trx-1 can be considered as a potential therapeutic molecule to treat heart failure. Nevertheless, its cleavage leading to the truncated pro-inflammatory isoform, Trx-80, could compromise its therapeutic use. To circumvent this problem, Trx-mimetic peptides have been developed. The aim of our study is to evaluate the impact of Trx-1, Trx-80 and Trx-mimetic peptides on heart failure in mice model and to identify the mechanisms involved in their effects. We studied the effect of Trx-1, Trx-80 and Trx-mimetic peptides on cultured neonatal mice cardiomyocytes and in vivo on adult mice with experimental myocardial infarction. To overexpress Trx-1 and Trx-80, we generated different AAV with a TnT cardiac chicken promoter, which is specific to the cardiomyocytes. Trx-1 and Trx-mimetic peptide improved cardiac functions such as cardiac contractility and dilatation. In contrast, AAV-Trx80 aggravated such parameters. Also, Trx-1 and Trx-mimetic peptide reduced the infarct size in mice. These results suggest that Trx-1 and Trx-mimetic peptide have benefit effects. In vitro studies showed that Trx-mimetic peptide increases cell proliferation and decreases protein carbonylation and intracellular level of ROS. There is no effect of cultured cardiomyocyte size. In conclusion, our results showed that Trx-1 and its mimetic peptide play a beneficial role on heart failure. Nevertheless, additional studies are needed to clarify the mechanism underlying such beneficial effect and identify other pathways.