Isorhapontigenin protects against doxorubicin-induced cardiotoxicity via increasing YAP1 expression  

作　　者：Panxia Wang Minghui Wang Yuehuai Hu Jianxing Chen Yanjun Cao Cui Liu Zhongkai Wu Juan Shen Jing Lu Peiqing Liu 

机构地区：[1]School of Pharmaceutical Sciences,Sun Yat-sen University,Guangzhou 5/0006,China [2]Department of Cardiac Surgery,First Affiliated Hospital,Sun Yat-sen University,Guangzhou 510080,China [3]Guangdong Provincial Key Laboratory of Pharmaceutical Bioactive Substances,Guangdong Pharmaceutical University,Guangzhou 510006,China [4]Guangdong Provincial Key Laboratory of New Drug Design and Evaluation,Sun Yat-sen University,Guangzhou 510006,China [5]Guangdong Provincial Engineering Laboratory of Druggability and New Drugs Evaluation,Guangzhou 510006,China

出　　处：《Acta Pharmaceutica Sinica B》2021年第3期680-693,共14页药学学报（英文版）

基　　金：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);Research and Industrialization team of Taxus chinensis var.mairel (2014YT02S044, China)。

摘　　要：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.

关 键 词：ISORHAPONTIGENIN YAP1 DOXORUBICIN CARDIOTOXICITY Cardiomyocytes apoptosis TEAD1 Connective tissue growth factor AMPHIREGULIN 

分 类 号：R965[医药卫生—药理学]