ErbB2 overexpression upregulates antioxidant enzymes, reduces basal levels of reactive oxygen species, and protects against doxorubicin cardiotoxicity

Frances Belmonte, Samarjit Das, Polina Sysa-Shah, Vidhya Sivakumaran, Brian Stanley, Xin Guo, Nazareno Paolocci, Miguel A. Aon, Masaki Nagane, Periannan Kuppusamy, Charles Steenbergen, Kathleen Gabrielson

Research output: Contribution to journalArticle

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 cardiacspecific overexpression of ErbB2 (ErbB2tg) 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 ErbB2tg hearts have lower ROS levels and less cellular death (P < 0.0001) following doxorubicin treatment. Analyzing antioxidant enzyme levels and activities, we found that ErbB2tg 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 ErbB2tg 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.

Original languageEnglish (US)
Pages (from-to)H1271-H1280
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume309
Issue number8
DOIs
StatePublished - Jan 1 2015

Keywords

  • ErbB2
  • Glutathione peroxidase
  • Mitochondria
  • NRTK
  • Reactive oxygen species

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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