关键词： AMPK, AMP-activated protein kinase AP-1, anti-microbial protein AREG, amphiregulin AUC/Dose, dose-normalized plasma exposures Amphiregulin Ang II, angiotensin II CO, cardiac output CTGF, connective tissue growth factor Cardiomyocytes apoptosis Cardiotoxicity Cmax/Dose, dose-normalized maximal plasma concentrations Connective tissue growth factor DAB, 3,3′-diaminobenzidine DMEM, Dulbecco's modified Eagle's medium Dob, dobutamine Dox, doxorubicin Doxorubicin EMT, epithelial mesenchymal transformation FOXO1, forkhead box class O1 FS, fractional shortening HE, hematoxylin–eosin ISO, isoproterenol Isor, isorhapontigenin Isorhapontigenin LVAW;d, left ventricular end-diastolic anterior wall thickness LVAW;s, left ventricular end-systolic anterior wall thickness LVEF, left ventricular ejection fraction LVID;d, left ventricular end-diastolic internal diameter LVID;s, left ventricular end-systolic internal diameter LVPW;d, left ventricular end-diastolic posterior wall thickness LVPW;s, left ventricular end-systolic posterior wall thickness MAPK, mitogen-activated protein kinase MI, myocardial infarction NF-κB, nuclear factor kappa-B NRCMs, neonatal rat cardiomyocytes P2Y12 receptor, ADP receptor PGC-1α, peroxisome proliferator-activated receptor γ coactivator-1α PMSF, phenylmethanesulfonyl fluoride PVDF, polyvinylidene fluoride ROS, reactive oxygen species SD, Sprague–Dawley SDS-PAGE, sodium dodecyl sulfate-polyacrylamide gel electrophoresis SESN2, sestrin2 TCF4, T-cell factor 4 TEAD, TEA domain transcription factor proteins TEAD1 TUNEL, TdT-mediated dUTP nick end labeling WGA, wheat germ agglutinin YAP1 YAP1, Yes-associated protein 1 qRT-PCR, quantitative real-time polymerase chain reaction sgRNAs, sequence guiding RNAs Δψm, mitochondrial membrane potential

来  源：   DOI：10.1016/j.apsb.2020.10.017   PDF(Sci-hub)   PDF(Pubmed)

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 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.
摘要：
作为一种有效的抗癌药物，多柔比星（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结构域1（TEAD1）相互作用，在细胞增殖和存活中起重要作用。然而,YAP1在Dox诱导的心肌病中的作用尚未见报道。在这项研究中,在患有扩张型心肌病和Dox诱导的体内和体外心脏毒性模型的临床人类衰竭心脏中，YAP1的表达降低。Yap1的异位表达以TEAD1依赖的方式显著阻断Dox诱导的心肌细胞凋亡。Isorhapontigenin（Isor）是二苯乙烯的新衍生物，负责广泛的生物过程。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。与Isor一起给药（30mg/kg/天，腹膜内，3周）显着保护小鼠免受Dox诱导的心脏毒性。有趣的是,Isor在体内和体外增加了Dox引起的YAP1抑制及其靶基因的表达。敲除或抑制Yap1阻断了Isor对Dox诱导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。
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