Astragalus polysaccharide restores autophagic flux and improves cardiomyocyte function in doxorubicin-induced cardiotoxicity.
Astragalus polysaccharide restores autophagic flux and improves cardiomyocyte function in doxorubicin-induced cardiotoxicity.
复制标题
黄芪多糖可恢复阿霉素诱导的心脏毒性中的自噬通量并改善心肌细胞功能。
DOI：
10.18632/oncotarget.13596
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发表时间：
2017-01-17
期刊：
影响因子：
--
通讯作者：
Li J
中科院分区：
文献类型：
--
作者：
Cao Y;Shen T;Huang X;Lin Y;Chen B;Pang J;Li G;Wang Q;Zohrabian S;Duan C;Ruan Y;Man Y;Wang S;Li J
阿霉素（阿霉素），蒽环类抗生素，通常用于治疗许多类型的实体和血液恶性肿瘤。不幸的是，由于相关的急性和慢性心脏毒性，多柔比星的临床使用受到限制。黄芪多糖（APS）是黄芪的提取物，具有较强的抗肿瘤和抗炎作用。然而，APS是否可以减轻化疗引起的心脏毒性目前尚不清楚。本研究采用阿霉素诱导的乳鼠心肌细胞损伤模型和小鼠心力衰竭模型，探讨黄芪多糖的作用。GFP-LC 3腺病毒介导的自噬囊泡试验、GFP和RFP串联标记的LC 3（tfLC 3）试验和Western印迹分析用于分析APS处理后心肌细胞的细胞功能和细胞信号转导变化。首先，阿霉素治疗导致C57 BL/6 J小鼠心力衰竭和心肌细胞凋亡增加，细胞自噬通量受到干扰。其次，APS恢复了阿霉素治疗的原代新生大鼠心室肌细胞和阿霉素诱导的心力衰竭小鼠模型中的自噬。第三，APS通过调节AMPK/mTOR通路减轻阿霉素诱导的心脏损伤。mTOR抑制剂雷帕霉素显著消除了APS的保护作用。这些结果表明，阿霉素可通过干扰心肌细胞自噬流，导致过度的细胞凋亡，从而诱导心力衰竭。APS可以恢复正常的自噬通量，通过调节AMPK/mTOR途径减轻阿霉素诱导的心脏毒性。
Doxorubicin (adriamycin), an anthracycline antibiotic, is commonly used to treat many types of solid and hematological malignancies. Unfortunately, clinical usage of doxorubicin is limited due to the associated acute and chronic cardiotoxicity. Previous studies demonstrated that Astragalus polysaccharide (APS), the extracts of Astragalus membranaceus, had strong anti-tumor activities and anti-inflammatory effects. However, whether APS could mitigate chemotherapy-induced cardiotoxicity is unclear thus far. We used a doxorubicin-induced neonatal rat cardiomyocyte injury model and a mouse heart failure model to explore the function of APS. GFP-LC3 adenovirus-mediated autophagic vesicle assays, GFP and RFP tandemly tagged LC3 (tfLC3) assays and Western blot analyses were performed to analyze the cell function and cell signaling changes following APS treatment in cardiomyocytes. First, doxorubicin treatment led to C57BL/6J mouse heart failure and increased cardiomyocyte apoptosis, with a disturbed cell autophagic flux. Second, APS restored autophagy in doxorubicin-treated primary neonatal rat ventricular myocytes and in the doxorubicin-induced heart failure mouse model. Third, APS attenuated doxorubicin-induced heart injury by regulating the AMPK/mTOR pathway. The mTOR inhibitor rapamycin significantly abrogated the protective effect of APS. These results suggest that doxorubicin could induce heart failure by disturbing cardiomyocyte autophagic flux, which may cause excessive cell apoptosis. APS could restore normal autophagic flux, ameliorating doxorubicin-induced cardiotoxicity by regulating the AMPK/mTOR pathway.