Astragalus polysaccharide restores autophagic flux and improves cardiomyocyte function in doxorubicin-induced cardiotoxicity
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Yuan Cao1, Tao Shen1, Xiuqing Huang1, Yajun Lin1, Beidong Chen1, Jing Pang1, Guoping Li1, Que Wang1, Sylvia Zohrabian2, Chao Duan3, Yang Ruan4, Yong Man1, Shu Wang1, Jian Li1
1Peking University Fifth School of Clinical Medicine, The MOH Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, Beijing, 100730, China
2Department of Cardiology, Boston Children’s Hospital, Enders 1250, Boston, MA, 02115, US
3Beijing Key Laboratory of Plant Resources Research and Development, Beijing Technology and Business University, Beijing 100037, China
4Beijing Anzhen Hospital, Capital Medical University and Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, 100029, China
Tao Shen, email: email@example.com
Jian Li, email: firstname.lastname@example.org
Keywords: astragalus polysaccharide, doxorubicin, cardiomyocyte, autophagy, AMPK/mTOR
Received: August 20, 2016 Accepted: November 08, 2016 Published: November 25, 2016
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.
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