title: Sirtuin-3 (SIRT3) Protein Attenuates Doxorubicin-induced Oxidative Stress and Improves Mitochondrial Respiration in H9c2 Cardiomyocytes.
abstract: Doxorubicin (DOX) is a chemotherapeutic agent effective in the treatment of many cancers. However, cardiac dysfunction caused by DOX limits its clinical use. DOX is believed to be harmful to cardiomyocytes by interfering with the mitochondrial phospholipid cardiolipin and causing inefficient electron transfer resulting in the production of reactive oxygen species (ROS). Sirtuin-3 (SIRT3) is a class III lysine deacetylase that is localized to the mitochondria and regulates mitochondrial respiration and oxidative stress resistance enzymes such as superoxide dismutase-2 (SOD2). The purpose of this study was to determine whether SIRT3 prevents DOX-induced mitochondrial ROS production. Administration of DOX to mice suppressed cardiac SIRT3 expression, and DOX induced a dose-dependent decrease in SIRT3 and SOD2 expression in H9c2 cardiomyocytes. SIRT3-null mouse embryonic fibroblasts produced significantly more ROS in the presence of DOX compared with wild-type cells. Overexpression of wild-type SIRT3 increased cardiolipin levels and rescued mitochondrial respiration and SOD2 expression in DOX-treated H9c2 cardiomyocytes and attenuated the amount of ROS produced following DOX treatment. These effects were absent when a deacetylase-deficient SIRT3 was expressed in H9c2 cells. Our results suggest that overexpression of SIRT3 attenuates DOX-induced ROS production, and this may involve increased SOD2 expression and improved mitochondrial bioenergetics. SIRT3 activation could be a potential therapy for DOX-induced cardiac dysfunction.
authors.affiliation: From the Department of Pharmacology and Therapeutics, Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Research Theme, Children's Hospital Research Institute of Manitoba, and.
authors.forename: Kyle G
authors.initials: KG
authors.lastname: Cheung
authors.affiliation: From the Department of Pharmacology and Therapeutics, Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Research Theme, Children's Hospital Research Institute of Manitoba, and.
authors.forename: Laura K
authors.initials: LK
authors.lastname: Cole
authors.affiliation: From the Department of Pharmacology and Therapeutics, Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Research Theme, Children's Hospital Research Institute of Manitoba, and.
authors.forename: Bo
authors.initials: B
authors.lastname: Xiang
authors.affiliation: Children's Nutrition Research Center, Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Keyun
authors.initials: K
authors.lastname: Chen
authors.affiliation: From the Department of Pharmacology and Therapeutics, Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Research Theme, Children's Hospital Research Institute of Manitoba, and.
authors.forename: Xiuli
authors.initials: X
authors.lastname: Ma
authors.affiliation: Department of Pathology, University of Manitoba, Winnipeg, Manitoba R3E 3P4, Canada and.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Myal
authors.affiliation: From the Department of Pharmacology and Therapeutics, Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Research Theme, Children's Hospital Research Institute of Manitoba, and.
authors.forename: Grant M
authors.initials: GM
authors.lastname: Hatch
authors.affiliation: Children's Nutrition Research Center, Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Tong
authors.affiliation: From the Department of Pharmacology and Therapeutics, Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Research Theme, Children's Hospital Research Institute of Manitoba, and vdolinsky@chrim.ca.
authors.forename: Vernon W
authors.initials: VW
authors.lastname: Dolinsky
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects* / Q000494:pharmacology; D002308:Cardiolipins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D004317:Doxorubicin / Q000009:adverse effects* / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006331:Heart Diseases / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D051379:Mice; D008929:Mitochondria, Heart / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000201:enzymology* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects* / Q000235:genetics; D010101:Oxygen Consumption / Q000187:drug effects* / Q000235:genetics; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D056566:Sirtuin 3 / Q000096:biosynthesis* / Q000235:genetics; D013482:Superoxide Dismutase / Q000096:biosynthesis / Q000235:genetics; D000099156:Superoxide Dismutase 2
chemical_list: D000903:Antibiotics, Antineoplastic; D002308:Cardiolipins; D004317:Doxorubicin; D017382:Reactive Oxygen Species; D056566:Sirtuin 3; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2; C525046:Sirt3 protein, mouse
keywords: Cardiomyocyte; Heart Failure; Mitochondria; Reactive Oxygen Species (ROS); Sirtuin