title: Astragalus polysaccharide restores autophagic flux and improves cardiomyocyte function in doxorubicin-induced cardiotoxicity.
abstract: 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.
authors.affiliation: Peking University Fifth School of Clinical Medicine, The MOH Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, Beijing, 100730, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Peking University Fifth School of Clinical Medicine, The MOH Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, Beijing, 100730, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Shen
authors.affiliation: Peking University Fifth School of Clinical Medicine, The MOH Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, Beijing, 100730, China.
authors.forename: Xiuqing
authors.initials: X
authors.lastname: Huang
authors.affiliation: Peking University Fifth School of Clinical Medicine, The MOH Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, Beijing, 100730, China.
authors.forename: Yajun
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Peking University Fifth School of Clinical Medicine, The MOH Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, Beijing, 100730, China.
authors.forename: Beidong
authors.initials: B
authors.lastname: Chen
authors.affiliation: Peking University Fifth School of Clinical Medicine, The MOH Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, Beijing, 100730, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Pang
authors.affiliation: Peking University Fifth School of Clinical Medicine, The MOH Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, Beijing, 100730, China.
authors.forename: Guoping
authors.initials: G
authors.lastname: Li
authors.affiliation: Peking University Fifth School of Clinical Medicine, The MOH Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, Beijing, 100730, China.
authors.forename: Que
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Boston Children's Hospital, Enders 1250, Boston, MA, 02115, USA.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Zohrabian
authors.affiliation: Beijing Key Laboratory of Plant Resources Research and Development, Beijing Technology and Business University, Beijing 100037, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Duan
authors.affiliation: Beijing Anzhen Hospital, Capital Medical University and Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, 100029, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Ruan
authors.affiliation: Peking University Fifth School of Clinical Medicine, The MOH Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, Beijing, 100730, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Man
authors.affiliation: Peking University Fifth School of Clinical Medicine, The MOH Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, Beijing, 100730, China.
authors.forename: Shu
authors.initials: S
authors.lastname: Wang
authors.affiliation: Peking University Fifth School of Clinical Medicine, The MOH Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, Beijing, 100730, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D027885:Astragalus propinquus / Q000737:chemistry*; D001343:Autophagy; D066126:Cardiotoxicity / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000633:toxicity*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006333:Heart Failure / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D006334:Heart Function Tests / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010936:Plant Extracts / Q000008:administration & dosage / Q000494:pharmacology; D011134:Polysaccharides / Q000008:administration & dosage* / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D010936:Plant Extracts; D011134:Polysaccharides; D004317:Doxorubicin; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
keywords: AMPK/mTOR; astragalus polysaccharide; autophagy; cardiomyocyte; doxorubicin