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Doxorubicin cardiomyopathy is ameliorated by acacetin via Sirt1-mediated activation of AMPK/Nrf2 signal molecules.
Journal of Cellular and Molecular Medicine ( IF 5.3 ) Pub Date : 2020-09-11 , DOI: 10.1111/jcmm.15859
Wei-Yin Wu 1 , Yu-Kai Cui 1 , Yi-Xiang Hong 1 , Yun-Da Li 1 , Yao Wu 1 , Gang Li 1 , Gui-Rong Li 1 , Yan Wang 1
Affiliation  

Doxorubicin cardiotoxicity is frequently reported in patients undergoing chemotherapy. The present study investigates whether cardiomyopathy induced by doxorubicin can be improved by the natural flavone acacetin in a mouse model and uncovers the potential molecular mechanism using cultured rat cardiomyoblasts. It was found that the cardiac dysfunction and myocardial fibrosis induced by doxorubicin were significantly improved by acacetin in mice with impaired Nrf2/HO‐1 and Sirt1/pAMPK molecules, which is reversed by acacetin treatment. Doxorubicin decreased cell viability and increased ROS production in rat cardiomyoblasts; these effects are significantly countered by acacetin (0.3‐3 μM) in a concentration‐dependent manner via activating Sirt1/pAMPK signals and enhancing antioxidation (Nrf2/HO‐1 and SOD1/SOD2) and anti‐apoptosis. These protective effects were abolished in cells with silencing Sirt1. The results demonstrate for the first time that doxorubicin cardiotoxicity is antagonized by acacetin via Sirt1‐mediated activation of AMPK/Nrf2 signal molecules, indicating that acacetin may be a drug candidate used clinically for protecting against doxorubicin cardiomyopathy.

中文翻译:

阿沙西汀可通过Sirt1介导的AMPK / Nrf2信号分子活化来改善阿霉素心肌病。

阿霉素心脏毒性经常在接受化疗的患者中报道。本研究调查了在小鼠模型中是否可以通过天然黄酮阿卡西汀改善阿霉素诱导的心肌病,并揭示了使用培养的大鼠心肌母细胞的潜在分子机制。研究发现,阿卡西汀可明显改善Nrf2 / HO-1和Sirt1 / pAMPK分子受损的小鼠中阿霉素引起的心功能不全和心肌纤维化,阿卡西汀可逆转这种不良反应。阿霉素可降低大鼠心肌母细胞的细胞活力并增加ROS的产生;通过激活Sirt1 / pAMPK信号并增强抗氧化作用(Nrf2 / HO-1和SOD1 / SOD2)和抗凋亡,阿沙西丁(0.3-3μM)以浓度依赖的方式显着抵消了这些作用。在沉默Sirt1的细胞中,这些保护作用被取消了。结果首次证明阿沙西汀通过Sirt1介导的AMPK / Nrf2信号分子活化激活阿霉素来对抗阿霉素的心脏毒性,这表明阿沙西汀可能是临床上用于预防阿霉素心肌病的候选药物。
更新日期:2020-10-22
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