title: ErbB2 overexpression upregulates antioxidant enzymes, reduces basal levels of reactive oxygen species, and protects against doxorubicin cardiotoxicity.
abstract: Levels of the HER2/ErbB2 protein in the heart are upregulated in some women during breast cancer therapy, and these women are at high risk for developing heart dysfunction after sequential treatment with anti-ErbB2/trastuzumab or doxorubicin. Doxorubicin is known to increase oxidative stress in the heart, and thus we considered the possibility that ErbB2 protein influences the status of cardiac antioxidant defenses in cardiomyocytes. In this study, we measured reactive oxygen species (ROS) in cardiac mitochondria and whole hearts from mice with cardiac-specific overexpression of ErbB2 (ErbB2(tg)) and found that, compared with control mice, high levels of ErbB2 in myocardium result in lower levels of ROS in mitochondria (P = 0.0075) and whole hearts (P = 0.0381). Neonatal cardiomyocytes isolated from ErbB2(tg) hearts have lower ROS levels and less cellular death (P < 0.0001) following doxorubicin treatment. Analyzing antioxidant enzyme levels and activities, we found that ErbB2(tg) hearts have increased levels of glutathione peroxidase 1 (GPx1) protein (P < 0.0001) and GPx activity (P = 0.0031) in addition to increased levels of two known GPx activators, c-Abl (P = 0.0284) and Arg (P < 0.0001). Interestingly, although mitochondrial ROS emission is reduced in the ErbB2(tg) hearts, oxygen consumption rates and complex I activity are similar to control littermates. Compared with these in vivo studies, H9c2 cells transfected with ErbB2 showed less cellular toxicity and produced less ROS (P < 0.0001) after doxorubicin treatment but upregulated GR activity (P = 0.0237) instead of GPx. Our study shows that ErbB2-dependent signaling contributes to antioxidant defenses and suggests a novel mechanism by which anticancer therapies involving ErbB2 antagonists can harm myocardial structure and function.
authors.affiliation: Program in Molecular and Translational Toxicology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland;
authors.forename: Frances
authors.initials: F
authors.lastname: Belmonte
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland;
authors.forename: Samarjit
authors.initials: S
authors.lastname: Das
authors.affiliation: Department of Molecular and Comparative Pathobiology, Johns Hopkins Medical Institutions, Baltimore, Maryland;
authors.forename: Polina
authors.initials: P
authors.lastname: Sysa-Shah
authors.affiliation: Division of Cardiology, Johns Hopkins Medical Institutions, Baltimore, Maryland; and.
authors.forename: Vidhya
authors.initials: V
authors.lastname: Sivakumaran
authors.affiliation: Division of Cardiology, Johns Hopkins Medical Institutions, Baltimore, Maryland; and.
authors.forename: Brian
authors.initials: B
authors.lastname: Stanley
authors.affiliation: Department of Molecular and Comparative Pathobiology, Johns Hopkins Medical Institutions, Baltimore, Maryland;
authors.forename: Xin
authors.initials: X
authors.lastname: Guo
authors.affiliation: Division of Cardiology, Johns Hopkins Medical Institutions, Baltimore, Maryland; and.
authors.forename: Nazareno
authors.initials: N
authors.lastname: Paolocci
authors.affiliation: Division of Cardiology, Johns Hopkins Medical Institutions, Baltimore, Maryland; and.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Aon
authors.affiliation: Department of Radiology, EPR Center for the Study of Viable Systems, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire.
authors.forename: Masaki
authors.initials: M
authors.lastname: Nagane
authors.affiliation: Department of Radiology, EPR Center for the Study of Viable Systems, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire.
authors.forename: Periannan
authors.initials: P
authors.lastname: Kuppusamy
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland;
authors.forename: Charles
authors.initials: C
authors.lastname: Steenbergen
authors.affiliation: Program in Molecular and Translational Toxicology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Molecular and Comparative Pathobiology, Johns Hopkins Medical Institutions, Baltimore, Maryland; kgabriel@jhmi.edu.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Gabrielson
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000970:Antineoplastic Agents / Q000633:toxicity*; D000975:Antioxidants / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000633:toxicity*; D005979:Glutathione Peroxidase / Q000378:metabolism*; D005980:Glutathione Reductase / Q000378:metabolism; D006331:Heart Diseases / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D000094765:Glutathione Peroxidase GPX1
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D004317:Doxorubicin; D005979:Glutathione Peroxidase; D005980:Glutathione Reductase; D011505:Protein-Tyrosine Kinases; D016315:Proto-Oncogene Proteins c-abl; D017382:Reactive Oxygen Species; D018719:Erb-b2 Receptor Tyrosine Kinases; D000094765:Glutathione Peroxidase GPX1; C426236:ARG tyrosine kinase; C524056:Erbb2 protein, mouse; C483804:Erbb2 protein, rat
keywords: ErbB2; glutathione peroxidase; mitochondria; nRTK; reactive oxygen species