The Protective Role of Glutathione on Doxorubicin-Induced Cardiotoxicity in Human Cardiac Progenitor Cells

Abstract

Abstract Cardiotoxicity caused by doxorubicin (DOX) is an important issue to consider for both patients and doctors who require DOX. DOX-induced cardiotoxicity is closely associated with cardiomyocyte death and dysfunction. To prevent DOX-induced cardiotoxicity, many studies have been conducted on new therapeutic strategies, including the discovery of novel functional modulators such as antioxidant drugs to restore the loss of function of transplanted or residual cardiac cells in the heart. We investigated whether glutathione (GSH), an antioxidant drug, has a protective effect against DOX-induced cardiotoxicity by decreasing ROS and unraveling the underlying molecular mechanisms. GSH clearly increased the viability of damaged human cardiac progenitor cells (hCPCs) treated with DOX. In addition, ROS generation and apoptosis induced by DOX treatment were significantly reduced. We also observed that GSH restored the capacity of hCPCs, as shown by the wound healing assay, transwell migration, and tube formation. We checked that GSH treatment restored the level of pERK, which increased in the DOX-treated group. The ERK inhibitor, U0126, increased the viability of damaged hCPCs. These data suggest that the restoration mechanism of GSH may be via the regulation of pERK signaling. We confirmed the effects of DOX and GSH using an in vivo model. As a result, GSH was confirmed to have a protective effect against DOX-induced cardiotoxicity through body weight, survival rate, histology, and mRNA level. Taken together, GSH prevents DOX-induced cardiotoxicity and regulates pERK signaling. GSH may be an effective therapeutic strategy for DOX-induced cardiotoxicity.