Original articles
Panxia Wang, Minghui Wang, Yuehuai Hu, Jianxing Chen, Yanjun Cao, Cui Liu, Zhongkai Wu, Juan Shen, Jing Lu, Peiqing Liu. Isorhapontigenin protects against doxorubicin-induced cardiotoxicity via increasing YAP1 expression[J]. Acta Pharmaceutica Sinica B, 2021, 11(3): 680-693

Isorhapontigenin protects against doxorubicin-induced cardiotoxicity via increasing YAP1 expression
Panxia Wanga, Minghui Wanga, Yuehuai Hua, Jianxing Chena, Yanjun Caoa, Cui Liua, Zhongkai Wue, Juan Shend, Jing Lua, Peiqing Liua,b,c
a School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China;
b Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-sen University, Guangzhou 510006, China;
c Guangdong Provincial Engineering Laboratory of Druggability and New Drugs Evaluation, Guangzhou 510006, China;
d Guangdong Provincial Key Laboratory of Pharmaceutical Bioactive Substances, Guangdong Pharmaceutical University, Guangzhou 510006, China;
e Department of Cardiac Surgery, First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China
Abstract:
As an effective anticancer drug, the clinical limitation of doxorubicin (Dox) is the time- and dose-dependent cardiotoxicity. Yes-associated protein 1 (YAP1) interacts with transcription factor TEA domain 1 (TEAD1) and plays an important role in cell proliferation and survival. However, the role of YAP1 in Dox-induced cardiomyopathy has not been reported. In this study, the expression of YAP1 was reduced in clinical human failing hearts with dilated cardiomyopathy and Dox-induced in vivo and in vitro cardiotoxic model. Ectopic expression of Yap1 significantly blocked Dox-induced cardiomyocytes apoptosis in TEAD1 dependent manner. Isorhapontigenin (Isor) is a new derivative of stilbene and responsible for a wide range of biological processes. Here, we found that Isor effectively relieved Doxinduced cardiomyocytes apoptosis in a dose-dependent manner in vitro. Administration with Isor (30 mg/kg/day, intraperitoneally, 3 weeks) significantly protected against Dox-induced cardiotoxicity in mice. Interestingly, Isor increased Dox-caused repression in YAP1 and the expression of its target genes in vivo and in vitro. Knockout or inhibition of Yap1 blocked the protective effects of Isor on Dox-induced cardiotoxicity. In conclusion, YAP1 may be a novel target for Dox-induced cardiotoxicity and Isor might be a new compound to fight against Dox-induced cardiotoxicity by increasing YAP1 expression.
Key words:    Isorhapontigenin    YAP1    Doxorubicin    Cardiotoxicity    Cardiomyocytes apoptosis    TEAD1    Connective tissue growth factor    Amphiregulin   
Received: 2020-06-21     Revised: 2020-08-22
DOI: 10.1016/j.apsb.2020.10.017
Funds: This research was supported by grants from the National Natural Science Foundation of China (81872860, 81803521, 81673433), National Major Special Projects for the Creation and Manufacture of New Drugs (2019ZX09301104, China), Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program (2017BT01Y093, China), National Engineering and Technology Research Center for New drug Druggability Evaluation (Seed Program of Guangdong Province, 2017B090903004, China), Natural Science Foundation of Guangdong Province (2019A1515010273, China), Foundation from Guangdong Traditional Medicine Bureau (20191060, China), Fundamental Research Funds for the Central Universities (19ykpy131, China) and Research and Industrialization team of Taxus chinensis var. mairel (2014YT02S044, China).
Corresponding author: Juan Shen, Jing Lu, Peiqing Liu     Email:liupq@mail.sysu.edu.cn;lujing28@mail.sysu.edu.cn;Shenjuan0412@126.com
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Panxia Wang
Minghui Wang
Yuehuai Hu
Jianxing Chen
Yanjun Cao
Cui Liu
Zhongkai Wu
Juan Shen
Jing Lu
Peiqing Liu

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