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

Hui Lin,Na Lin,Liping Meng,Feidan Gao,Jufang Chi,Hangqi Luo,Tingjuan Ni,Jie Zhang,Xiatian Liu,Hangyuan Guo

doi:10.1111/jcmm.14466

Abstract

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.

Highlights

Doxorubicin (DOX), an effective anthracycline, is a chemotherapeu‐ tic drug commonly used to treat a wide range of cancers
To reveal the mechanisms underlying the action of Yellow wine polyphenolic compounds (YWPC), we examined whether YWPC could suppress DOX‐induced oxidative stress through the regulation of Nrf[2] signalling pathway
We demonstrated that YWPC effectively alleviated DOX‐induced cardiotoxicity by inhibiting oxidative stress through activation of Nrf[2] pathway

Summary

| INTRODUCTION

Doxorubicin (DOX), an effective anthracycline, is a chemotherapeu‐ tic drug commonly used to treat a wide range of cancers. A plenty of studies have identified that nuclear factor‐E2‐related factor‐2 (Nrf2) is implicated as a master regulator in the cellular response to oxidative stress.[16] emerging evidence suggests the importance of inflamma‐ tion in the pathogenesis of DOX‐induced cardiotoxicity[17,18] and Nrf[2] has an anti‐inflammatory effect.[19] several studies have revealed that the deactivation of Nrf[2] signalling was involved in DOX‐induced cardiotoxicity,[17,20] whether Nrf[2] activation could help to alleviate DOX‐induced cardiac fibrosis are rarely studied.[21]. To reveal the mechanisms underlying the action of YWPC, we examined whether YWPC could suppress DOX‐induced oxidative stress through the regulation of Nrf[2] signalling pathway

| MATERIALS AND METHODS

| DISCUSSION

Findings

CONFLICT OF INTEREST