title: Nrf2 deficiency exaggerates doxorubicin-induced cardiotoxicity and cardiac dysfunction.
abstract: The anticancer therapy of doxorubicin (Dox) has been limited by its acute and chronic cardiotoxicity. In addition to a causative role of oxidative stress, autophagy appears to play an important role in the regulation of Dox-induced cardiotoxicity. However, the underlying mechanisms remain unclear. Accordingly, we explored a role of nuclear factor erythroid-2 related factor 2 (Nrf2) in Dox-induced cardiomyopathy with a focus on myocardial oxidative stress and autophagic activity. In wild type (WT) mice, a single intraperitoneal injection of 25 mg/kg Dox rapidly induced cardiomyocyte necrosis and cardiac dysfunction, which were associated with oxidative stress, impaired autophagy, and accumulated polyubiquitinated protein aggregates. However, these Dox-induced adverse effects were exaggerated in Nrf2 knockout (Nrf2(-/-)) mice. In cultured cardiomyocytes, overexpression of Nrf2 increased the steady levels of LC3-II, ameliorated Dox-induced impairment of autophagic flux and accumulation of ubiquitinated protein aggregates, and suppressed Dox-induced cytotoxicity, whereas knockdown of Nrf2 exerted opposite effects. Moreover, the exaggerated adverse effects in Dox-intoxicated Nrf2 depleted cardiomyocytes were dramatically attenuated by forced activation of autophagy via overexpression of autophagy related gene 5 (Atg5). Thus, these results suggest that Nrf2 is likely an endogenous suppressor of Dox-induced cardiotoxicity by controlling both oxidative stress and autophagy in the heart.
authors.affiliation: Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan 250012, China ; Department of Cell Biology and Anatomy, University of South Carolina, School of Medicine, Columbia, SC 29208, USA.
authors.forename: Siying
authors.initials: S
authors.lastname: Li
authors.affiliation: Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan 250012, China ; Department of Cell Biology and Anatomy, University of South Carolina, School of Medicine, Columbia, SC 29208, USA.
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Wang
authors.affiliation: Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan 250012, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Niu
authors.affiliation: Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan 250012, China ; Department of Cell Biology and Anatomy, University of South Carolina, School of Medicine, Columbia, SC 29208, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan 250012, China ; Department of Cell Biology and Anatomy, University of South Carolina, School of Medicine, Columbia, SC 29208, USA.
authors.forename: Bin
authors.identifier: 0000-0002-2050-3284
authors.initials: B
authors.lastname: Li
authors.affiliation: Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan 250012, China ; Department of Cell Biology and Anatomy, University of South Carolina, School of Medicine, Columbia, SC 29208, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Shao
authors.affiliation: Department of Cell Biology and Anatomy, University of South Carolina, School of Medicine, Columbia, SC 29208, USA.
authors.forename: Yimu
authors.identifier: 0000-0002-8934-0487
authors.initials: Y
authors.lastname: Lai
authors.affiliation: Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan 250012, China.
authors.forename: Huanjie
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Cell Biology and Anatomy, University of South Carolina, School of Medicine, Columbia, SC 29208, USA.
authors.forename: Joseph S
authors.identifier: 0000-0003-3075-1422
authors.initials: JS
authors.lastname: Janicki
authors.affiliation: Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan 250012, China.
authors.forename: Xing Li
authors.identifier: 0000-0002-4104-7820
authors.initials: XL
authors.lastname: Wang
authors.affiliation: Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan 250012, China ; Department of Cell Biology and Anatomy, University of South Carolina, School of Medicine, Columbia, SC 29208, USA.
authors.forename: Dongqi
authors.initials: D
authors.lastname: Tang
authors.affiliation: Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan 250012, China ; Department of Cell Biology and Anatomy, University of South Carolina, School of Medicine, Columbia, SC 29208, USA.
authors.forename: Taixing
authors.identifier: 0000-0002-9528-7299
authors.initials: T
authors.lastname: Cui
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects; D000071187:Autophagy-Related Protein 5; D009202:Cardiomyopathies / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D066126:Cardiotoxicity; D002478:Cells, Cultured; D004317:Doxorubicin / Q000633:toxicity*; D006321:Heart / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009336:Necrosis; D018384:Oxidative Stress / Q000187:drug effects
chemical_list: C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D008869:Microtubule-Associated Proteins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D004317:Doxorubicin