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Atorvastatin protects cardiomyocyte from doxorubicin toxicity by modulating survivin expression through FOXO1 inhibition.
Journal of Molecular and Cellular Cardiology ( IF 4.9 ) Pub Date : 2019-12-19 , DOI: 10.1016/j.yjmcc.2019.12.007
Jaewon Oh 1 , Beom Seob Lee 2 , Gibbeum Lim 3 , Heejung Lim 3 , Chan Joo Lee 1 , Sungha Park 3 , Sang-Hak Lee 3 , Ji Hyung Chung 4 , Seok-Min Kang 3
Affiliation  

BACKGROUND Survivin has an anti-apoptotic effect against anthracycline-induced cardiotoxicity. Clinically, statin use is associated with a lower risk for heart failure in breast cancer patients with anthracycline chemotherapy. So, the purpose of our study was to investigate whether survivin mediates the protective effect of statin against anthracycline-induced cardiotoxicity. METHODS Mice were treated once a week with 5 mg/kg doxorubicin for 4 weeks with or without atorvastatin 20 mg/kg every day then heart tissues were analyzed. Molecular and cellular biology analyses were performed with H9c2 cell lysates. RESULTS Doxorubicin suppressed survivin expression via activation of FOXO1 in H9c2 cardiomyocytes. Whereas, atorvastatin inhibited FOXO1 by increasing phosphorylation and inhibiting nuclear localization. Doxorubicin induced FOXO1 binding to STAT3 and prevented STAT3 from interacting with Sp1. However, atorvastatin inhibited these interactions and stabilized STAT3/Sp1 transcription complex. Chromatin immunoprecipitation analysis demonstrated that doxorubicin decreased STAT3/Sp1 complex binding to survivin promoter, whereas atorvastatin stabilized this binding. In mouse model, atorvastatin rescued doxorubicin-induced reduction of survivin expression and of heart function measured by cardiac magnetic resonance imaging. CONCLUSIONS Our study suggested a new pathophysiologic mechanism that survivin mediated protective effect of atorvastatin against doxorubicin-induced cardiotoxicity via FOXO1/STAT3/Sp1 transcriptional network.

中文翻译:

阿托伐他汀通过抑制FOXO1调节survivin表达,从而保护心肌细胞免受阿霉素毒性。

背景技术Survivin具有抗蒽环类药物引起的心脏毒性的抗凋亡作用。在临床上,他汀类药物的使用与蒽环类化疗的乳腺癌患者发生心力衰竭的风险较低相关。因此,我们的研究目的是研究生存素是否介导他汀类药物对蒽环类药物引起的心脏毒性的保护作用。方法每天用5 mg / kg阿霉素对小鼠进行每周一次的治疗,连续4周,每天使用或不使用阿托伐他汀20 mg / kg,然后对心脏组织进行分析。分子和细胞生物学分析是用H9c2细胞裂解物进行的。结果阿霉素通过激活H9c2心肌细胞中的FOXO1抑制survivin表达。而阿托伐他汀通过增加磷酸化和抑制核定位来抑制FOXO1。阿霉素诱导FOXO1与STAT3结合,并阻止STAT3与Sp1相互作用。但是,阿托伐他汀抑制了这些相互作用并稳定了STAT3 / Sp1转录复合体。染色质免疫沉淀分析表明,阿霉素可降低STAT3 / Sp1复合物与survivin启动子的结合,而阿托伐他汀可稳定这种结合。在小鼠模型中,阿托伐他汀挽救了阿霉素诱导的survivin表达减少和心功能降低,这是通过心脏磁共振成像测定的。结论我们的研究提出了一种新的病理生理机制,即生存素通过FOXO1 / STAT3 / Sp1转录网络介导阿托伐他汀对阿霉素诱导的心脏毒性的保护作用。阿托伐他汀抑制这些相互作用并稳定STAT3 / Sp1转录复合体。染色质免疫沉淀分析表明,阿霉素可降低STAT3 / Sp1复合物与survivin启动子的结合,而阿托伐他汀可稳定这种结合。在小鼠模型中,阿托伐他汀挽救了阿霉素诱导的survivin表达减少和心功能降低,这是通过心脏磁共振成像测定的。结论我们的研究提出了一种新的病理生理机制,即生存素通过FOXO1 / STAT3 / Sp1转录网络介导阿托伐他汀对阿霉素诱导的心脏毒性的保护作用。阿托伐他汀抑制这些相互作用并稳定STAT3 / Sp1转录复合体。染色质免疫沉淀分析表明,阿霉素可降低STAT3 / Sp1复合物与survivin启动子的结合,而阿托伐他汀可稳定这种结合。在小鼠模型中,阿托伐他汀挽救了阿霉素诱导的survivin表达减少和心功能降低,这是通过心脏磁共振成像测定的。结论我们的研究提出了一种新的病理生理机制,即生存素通过FOXO1 / STAT3 / Sp1转录网络介导阿托伐他汀对阿霉素诱导的心脏毒性的保护作用。阿托伐他汀挽救了阿霉素诱导的survivin表达和心脏功能的降低,并通过心脏磁共振成像进行了测量。结论我们的研究提出了一种新的病理生理机制,即生存素通过FOXO1 / STAT3 / Sp1转录网络介导阿托伐他汀对阿霉素诱导的心脏毒性的保护作用。阿托伐他汀挽救了阿霉素诱导的survivin表达和心脏功能的降低,并通过心脏磁共振成像进行了测量。结论我们的研究提出了一种新的病理生理机制,即生存素通过FOXO1 / STAT3 / Sp1转录网络介导阿托伐他汀对阿霉素诱导的心脏毒性的保护作用。
更新日期:2019-12-19
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