title: Mitochondrial ROS-induced ERK1/2 activation and HSF2-mediated AT1R upregulation are required for doxorubicin-induced cardiotoxicity.
abstract: Doxorubicin (DOX), one useful chemotherapeutic agent, is limited in clinical use because of its serious cardiotoxicity. Growing evidence suggests that angiotensin receptor blockers (ARBs) have cardioprotective effects in DOX-induced cardiomyopathy. However, the detailed mechanisms underlying the action of ARBs on the prevention of DOX-induced cardiomyocyte cell death have yet to be investigated. Our results showed that angiotensin II receptor type I (AT1R) plays a critical role in DOX-induced cardiomyocyte apoptosis. We found that MAPK signaling pathways, especially ERK1/2, participated in modulating AT1R gene expression through DOX-induced mitochondrial ROS release. These results showed that several potential heat shock binding elements (HSE), which can be recognized by heat shock factors (HSFs), located at the AT1R promoter region. HSF2 markedly translocated from the cytoplasm to the nucleus when cardiomyocytes were damaged by DOX. Furthermore, the DNA binding activity of HSF2 was enhanced by DOX via deSUMOylation. Overexpression of HSF2 enhanced DOX-induced cardiomyocyte cell death as well. Taken together, we found that DOX induced mitochondrial ROS release to activate ERK-mediated HSF2 nuclear translocation and AT1R upregulation causing DOX-damaged heart failure in vitro and in vivo.
authors.affiliation: Translation Research Core, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Chih-Yang
authors.identifier: http://orcid.org/0000-0002-0266-3233
authors.initials: CY
authors.lastname: Huang
authors.affiliation: Graduate Institute of Basic Medical Science, China Medical University, Taichung.
authors.forename: Jia-Yi
authors.initials: JY
authors.lastname: Chen
authors.affiliation: Department of Sports Sciences, University of Taipei, Taipei, Taiwan.
authors.forename: Chia-Hua
authors.initials: CH
authors.lastname: Kuo
authors.affiliation: Division of Cardiology, China Medical University Hospital, Taichung, Taiwan.|School of Chinese Medicine, China Medical University, Taichung, Taiwan.
authors.forename: Pei-Ying
authors.initials: PY
authors.lastname: Pai
authors.affiliation: Division of Cardiology, China Medical University Hospital, Taichung, Taiwan.|School of Chinese Medicine, China Medical University, Taichung, Taiwan.|Chinese Medicine Department, China Medical University Beigang Hospital, Taiwan.
authors.forename: Tsung-Jung
authors.initials: TJ
authors.lastname: Ho
authors.affiliation: Graduate Institute of Basic Medical Science, China Medical University, Taichung.|Biomaterials Translational Research Center, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Tung-Sheng
authors.initials: TS
authors.lastname: Chen
authors.affiliation: Chinese Medicine Department, China Medical University Beigang Hospital, Taiwan.
authors.forename: Fu-Jen
authors.initials: FJ
authors.lastname: Tsai
authors.affiliation: Department of Biotechnology, Bharathiar University, Coimbatore, India.
authors.forename: Vijaya V
authors.initials: VV
authors.lastname: Padma
authors.affiliation: Department of Biological Science and Technology, China Medical University, Taichung, Taiwan.
authors.forename: Wei-Wen
authors.initials: WW
authors.lastname: Kuo
authors.affiliation: Graduate Institute of Basic Medical Science, China Medical University, Taichung.|Division of Cardiology, China Medical University Hospital, Taichung, Taiwan.|School of Chinese Medicine, China Medical University, Taichung, Taiwan.|Department of Health and Nutrition Biotechnology, Asia University, Taichung.
authors.forename: Chih-Yang
authors.identifier: http://orcid.org/0000-0003-2347-0411
authors.initials: CY
authors.lastname: Huang
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D000903:Antibiotics, Antineoplastic; D017209:Apoptosis; D001665:Binding Sites; D066126:Cardiotoxicity; D002460:Cell Line; D004195:Disease Models, Animal; D004317:Doxorubicin; D004789:Enzyme Activation; D006331:Heart Diseases / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D006360:Heat-Shock Proteins / Q000378:metabolism*; D008929:Mitochondria, Heart / Q000201:enzymology* / Q000473:pathology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000201:enzymology* / Q000473:pathology; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D011921:Rats, Inbred WKY; D017382:Reactive Oxygen Species / Q000378:metabolism*; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D058207:Sumoylation; D014157:Transcription Factors / Q000378:metabolism*; D014162:Transfection; D015854:Up-Regulation
chemical_list: D000903:Antibiotics, Antineoplastic; D006360:Heat-Shock Proteins; C568775:Hsf2 protein, rat; D017382:Reactive Oxygen Species; D044140:Receptor, Angiotensin, Type 1; D014157:Transcription Factors; D004317:Doxorubicin; C535149:Mapk1 protein, rat; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
keywords: ARB; ERK; HSF2; cardiotoxicity; doxorubicin