Endothelial progenitor cell (EPC)-based stem cell therapy is a promising therapeutic strategy for vascular diseases. However, continuous in vitro expansion for clinical studies induces the loss of EPC functionality due to aging. In this study, we investigated the effects of StemRegenin-1 (SR-1), an antagonist of aryl hydrocarbon receptor (AhR), on replicative senescence in EPCs. We found that SR-1 maintained the expression of EPC surface markers, including stem cell markers, such as CD34, c-Kit, and CXCR4. Moreover, SR-1 long-term-treated EPCs preserved their characteristics. Subsequently, we demonstrated that SR-1 showed that aging phenotypes were reduced through senescence-associated phenotypes, such as β-galactosidase activity, SMP30, p21, p53, and senescence-associated secretory phenotype (SASP). SR-1 treatment also increased the proliferation, migration, and tube-forming capacity of senescent EPCs. SR-1 inhibited the AhR-mediated cytochrome P450 (CYP)1A1 expression, reactive-oxygen species (ROS) production, and DNA damage under oxidative stress conditions in EPCs. Furthermore, as a result of CYP1A1-induced ROS inhibition, it was found that accumulated intracellular ROS were decreased in senescent EPCs. Finally, an in vivo Matrigel plug assay demonstrated drastically enhanced blood vessel formation via SR-1-treated EPCs. In summary, our results suggest that SR-1 contributes to the protection of EPCs against cellular senescence.
This study investigated the protective effect of glutathione (GSH), an antioxidant drug, against doxorubicin (DOX)-induced cardiotoxicity. Human cardiac progenitor cells (hCPCs) treated with DOX (250 to 500 nM) showed increased viability and reduced ROS generation and apoptosis with GSH treatment (0.1 to 1 mM) for 24 h. In contrast to the 500 nM DOX group, pERK levels were restored in the group co-treated with GSH and suppression of ERK signaling improved hCPCs’ survival. Similarly to the previous results, the reduced potency of hCPCs in the 100 nM DOX group, which did not affect cell viability, was ameliorated by co-treatment with GSH (0.1 to 1 mM). Furthermore, GSH was protected against DOX-induced cardiotoxicity in the in vivo model (DOX 20 mg/kg, GSH 100 mg/kg). These results suggest that GSH is a potential therapeutic strategy for DOX-induced cardiotoxicity, which performs its function via ROS reduction and pERK signal regulation.
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.
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