title: UVRAG Deficiency Exacerbates Doxorubicin-Induced Cardiotoxicity.
abstract: Doxorubicin (DOX) is an effective chemotherapeutic drug in the treatment of various types of cancers. However, its clinical application has been largely limited by potential development of cardiotoxicity. Previously we have shown that ultra-violet radiation resistance-associated gene (UVRAG), an autophagy-related protein, is essential for the maintenance of autophagic flux in the heart under physiological conditions. Here, we sought to determine the role of UVRAG-mediated autophagy in DOX-induced cardiotoxicity. Mouse models of acute or chronic DOX-induced cardiotoxicity were established. UVRAG deficiency exacerbated DOX-induced mortality and cardiotoxicity manifested by increased cytoplasmic vacuolization, enhanced collagen accumulation, elevated serum activities of lactate dehydrogenase and myocardial muscle creatine kinase, higher ROS levels, aggravated apoptosis and more depressed cardiac function. Autophagic flux was impaired in DOX-induced cardiotoxicity. UVRAG deficiency aggravated impaired autophagic flux in DOX-induced cardiotoxicity. Intermittent fasting restored autophagy and ameliorated pathological alterations of DOX-induced cardiotoxicity. Collectively, our data suggest that UVRAG deficiency exacerbates DOX-induced cardiotoxicity, at least in part, through aggravation of DOX-induced impaired autophagic flux. Intermittent fasting, which restores blunted autophagic flux and ameliorates pathology in the mouse models of DOX-induced cardiotoxicity, may be used as a potential preventive or therapeutic approach for DOX cardiotoxicity.
authors.affiliation: Bio-X-Renji Hospital Research Center, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Lin
authors.initials: L
authors.lastname: An
authors.affiliation: Bio-X-Renji Hospital Research Center, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Xiao-Wen
authors.initials: XW
authors.lastname: Hu
authors.affiliation: Bio-X-Renji Hospital Research Center, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Shasha
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Bio-X-Renji Hospital Research Center, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Xiaowen
authors.initials: X
authors.lastname: Hu
authors.affiliation: Bio-X-Renji Hospital Research Center, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Zongpei
authors.initials: Z
authors.lastname: Song
authors.affiliation: Bio-X-Renji Hospital Research Center, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Amber
authors.initials: A
authors.lastname: Naz
authors.affiliation: Bio-X-Renji Hospital Research Center, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Zhenguo
authors.initials: Z
authors.lastname: Zi
authors.affiliation: Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Wu
authors.affiliation: Bio-X-Renji Hospital Research Center, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.|Collaborative Innovation Center of Genetics and Development, China.
authors.forename: Can
authors.initials: C
authors.lastname: Li
authors.affiliation: Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
authors.forename: Yunzeng
authors.initials: Y
authors.lastname: Zou
authors.affiliation: Bio-X-Renji Hospital Research Center, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.|Collaborative Innovation Center of Genetics and Development, China.
authors.forename: Lin
authors.initials: L
authors.lastname: He
authors.affiliation: Bio-X-Renji Hospital Research Center, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.|Collaborative Innovation Center of Genetics and Development, China.
authors.forename: Hongxin
authors.initials: H
authors.lastname: Zhu
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects*; D066126:Cardiotoxicity; D004317:Doxorubicin / Q000009:adverse effects*; D051379:Mice; D016019:Survival Analysis; D025521:Tumor Suppressor Proteins / Q000172:deficiency*
chemical_list: D000903:Antibiotics, Antineoplastic; D025521:Tumor Suppressor Proteins; C512859:UVRAG protein, mouse; D004317:Doxorubicin