title: Alginate Oligosaccharide Prevents Acute Doxorubicin Cardiotoxicity by Suppressing Oxidative Stress and Endoplasmic Reticulum-Mediated Apoptosis.
abstract: Doxorubicin (DOX) is a highly potent chemotherapeutic agent, but its usage is limited by dose-dependent cardiotoxicity. DOX-induced cardiotoxicity involves increased oxidative stress and activated endoplasmic reticulum-mediated apoptosis. Alginate oligosaccharide (AOS) is a non-immunogenic, non-toxic and biodegradable polymer, with anti-oxidative, anti-inflammatory and anti-endoplasmic reticulum stress properties. The present study examined whether AOS pretreatment could protect against acute DOX cardiotoxicity, and the underlying mechanisms focused on oxidative stress and endoplasmic reticulum-mediated apoptosis. We found that AOS pretreatment markedly increased the survival rate of mice insulted with DOX, improved DOX-induced cardiac dysfunction and attenuated DOX-induced myocardial apoptosis. AOS pretreatment mitigated DOX-induced cardiac oxidative stress, as shown by the decreased expressions of gp91 (phox) and 4-hydroxynonenal (4-HNE). Moreover, AOS pretreatment significantly decreased the expression of Caspase-12, C/EBP homologous protein (CHOP) (markers for endoplasmic reticulum-mediated apoptosis) and Bax (a downstream molecule of CHOP), while up-regulating the expression of anti-apoptotic protein Bcl-2. Taken together, these findings identify AOS as a potent compound that prevents acute DOX cardiotoxicity, at least in part, by suppression of oxidative stress and endoplasmic reticulum-mediated apoptosis.
authors.affiliation: Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai 200032, China. qy_junjie@163.com.|Department of Cardiology, The Affiliated Hospital of Qingdao University, 16 Jiang Su Road, Qingdao 266003, China. qy_junjie@163.com.
authors.forename: Jun-Jie
authors.initials: JJ
authors.lastname: Guo
authors.affiliation: Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai 200032, China. mllsdjn@126.com.
authors.forename: Lei-Lei
authors.initials: LL
authors.lastname: Ma
authors.affiliation: Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai 200032, China. hongtaoshi@126.com.
authors.forename: Hong-Tao
authors.initials: HT
authors.lastname: Shi
authors.affiliation: Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai 200032, China. zhujianbing543@163.com.
authors.forename: Jian-Bing
authors.initials: JB
authors.lastname: Zhu
authors.affiliation: Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai 200032, China. everwoo@sina.com.
authors.forename: Jian
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai 200032, China. zhiwen.d@gmail.com.
authors.forename: Zhi-Wen
authors.initials: ZW
authors.lastname: Ding
authors.affiliation: Department of Cardiology, The Affiliated Hospital of Qingdao University, 16 Jiang Su Road, Qingdao 266003, China. any@medmail.com.cn.
authors.forename: Yi
authors.initials: Y
authors.lastname: An
authors.affiliation: Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai 200032, China. zou.yunzeng@zs-hospital.sh.cn.|Institute of Biomedical Science, Fudan University, Shanghai 200032, China. zou.yunzeng@zs-hospital.sh.cn.
authors.forename: Yun-Zeng
authors.initials: YZ
authors.lastname: Zou
authors.affiliation: Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai 200032, China. jbge@zs-hospital.sh.cn.|Institute of Biomedical Science, Fudan University, Shanghai 200032, China. jbge@zs-hospital.sh.cn.
authors.forename: Jun-Bo
authors.initials: JB
authors.lastname: Ge
mesh_terms: D000447:Aldehydes / Q000378:metabolism; D000464:Alginates; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D015415:Biomarkers; D066126:Cardiotoxicity / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D053454:Caspase 12 / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004317:Doxorubicin / Q000009:adverse effects / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004721:Endoplasmic Reticulum / Q000187:drug effects; D020723:Glucuronic Acid; D006603:Hexuronic Acids; D051379:Mice; D009844:Oligosaccharides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D011971:Receptors, Immunologic / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization; D051742:Transcription Factor CHOP / Q000378:metabolism
chemical_list: D000447:Aldehydes; D000464:Alginates; D051017:Apoptosis Regulatory Proteins; D015415:Biomarkers; D006603:Hexuronic Acids; D009844:Oligosaccharides; C105949:Pirb protein, mouse; D011971:Receptors, Immunologic; D051742:Transcription Factor CHOP; D004317:Doxorubicin; D020723:Glucuronic Acid; D053454:Caspase 12; C027576:4-hydroxy-2-nonenal
keywords: alginate oligosaccharide; apoptosis; doxorubicin cardiotoxicity; endoplasmic reticulum; oxidative stress