Mesenchymal stem cells attenuate doxorubicin-induced cellular senescence through the VEGF/Notch/TGF-β signaling pathway in H9c2 cardiomyocytes

Abstract

The clinical use of doxorubicin (Dox) is limited by its cardiotoxicity. The fundamental changes it induces include interstitial myocardial fibrosis and the appearance of senescent cardiomyocytes. Mesenchymal stem cell (MSC)-based therapies have also been reported to modulate cellular senescence, and have been used effectively to treat age-related cardiovascular diseases. In the present study, the Transwell system was used to coculture H9c2 cells with MSCs, and their proliferation and viability were assessed. The expression of senescence-related genes p53 and p16, and telomere length were measured using reverse transcription-quantitative polymerase chain reaction analysis, and the Jagged-1/Notch-1 signaling pathway was detected using western blot analysis. The results revealed that Dox induced the senescence of H9c2 cells, characterized by a low proliferation rate, poor viability, reduced telomere length and impaired telomerase activity, and by marked increases in the expression of p53 and p16. By contrast, when cocultured with MSCs in the presence of Dox, H9c2 cell proliferation and viability increased, whereas the expression levels of p53 and p16 decreased, and telomere length and telomerase activity increased. The mechanism underlying the antisenescence function of MSCs was clarified, which involved the vascular endothelial growth factor (VEGF)/Jagged-1/Notch-1/transforming growth factor-β1 (TGF-β1) signaling pathway. It was confirmed that inhibiting VEGF, or silencing Jagged-1 or Notch-1 with small interfering RNA, or using recombinant TGF-β1 eliminated the antisenescence effects of MSCs on the Dox-treated H9c2 cells. The results revealed that MSCs rescued H9c2 cells from Dox-induced senescence through the release of VEGF, which activated the Jagged-1/Notch-1 signaling pathway, leading to the inhibition of TGF-β1 release. Therefore, treatment with MSCs may have important therapeutic implications on the attenuation of cardiotoxicity in patients with cancer treated with Dox.