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 Dox-induced 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.

作为有效的抗癌药物，阿霉素（Dox）的临床局限性是时间和剂量依赖性的心脏毒性。Yes相关蛋白1（YAP1）与转录因子TEA域1（TEAD1）相互作用，并在细胞增殖和存活中起重要作用。然而，尚未报道YAP1在Dox诱导的心肌病中的作用。在这项研究中，YAP1的表达在具有扩张型心肌病和Dox诱导的体内和体外心脏毒性模型的临床人衰竭心脏中降低。Yap1的异位表达以TEAD1依赖性方式显着阻断Dox诱导的心肌细胞凋亡。异皂甙元（Isor）是一种新的二苯乙烯衍生物，负责广泛的生物学过程。在这里，我们发现Isor在体外以剂量依赖的方式有效缓解了Dox诱导的心肌细胞凋亡。用Isor（30 mg / kg / day，腹膜内注射，持续3周）给药可显着预防Dox诱导的小鼠心脏毒性。有趣的是，Isor在体内和体外提高了YAP1中Dox引起的抑制及其靶基因的表达。敲除或抑制Yap1阻断了Isor对Dox引起的心脏毒性的保护作用。总之，YAP1可能是Dox诱导的心脏毒性的新靶标，而Isor可能是通过增加YAP1表达来对抗Dox诱导的心脏毒性的新化合物。