Yellow Wine Polyphenolic Compounds prevents Doxorubicin-induced cardiotoxicity through activation of the Nrf2 signalling pathway

Doxorubicin (DOX) is considered as the major culprit in chemotherapy-induced cardiotoxicity. Yellow wine polyphenolic compounds (YWPC), which are full of Polyphenols, have beneficial effects on Cardiovascular Disease. However, their role in DOX-induced cardiotoxicity is poorly understood. Due to their antioxidant property, we have been suggested that YWPC could prevent DOX-induced cardiotoxicity. In this study, we found that YWPC treatment (30 mg/kg/day) significantly improved DOX-induced cardiac hypertrophy and cardiac dysfunction. YWPC alleviated DOX-induced increase in oxidative stress levels, reduction in endogenous antioxidant enzyme activities and inflammatory response. Besides, administration of YWPC could prevent DOX-induced mitochondria-mediated cardiac Apoptosis. Mechanistically, we found that YWPC attenuated DOX-induced Reactive Oxygen Species (ROS) and down-regulation of transforming growth factor beta 1 (TGF-β1)/SMAD3 pathway by promoting nuclear factor (erythroid-derived 2)-like 2 (Nrf2) nucleus translocation in cultured H9C2 cardiomyocytes. Additionally, YWPC against DOX-induced TGF-β1 up-regulation were abolished by Nrf2 knockdown. Further studies revealed that YWPC could inhibit DOX-induced cardiac fibrosis through inhibiting TGF-β/smad3-mediated ECM synthesis. Collectively, our results revealed that YWPC might be effective in mitigating DOX-induced cardiotoxicity by Nrf2-dependent down-regulation of the TGF-β/SMAD3 pathway.