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Identification of the molecular basis of doxorubicin-induced cardiotoxicity

Nature Medicine volume 18, pages 1639–1642 (2012)Cite this article

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Abstract

Doxorubicin is believed to cause dose-dependent cardiotoxicity through redox cycling and the generation of reactive oxygen species (ROS). Here we show that cardiomyocyte-specific deletion of Top2b (encoding topoisomerase-IIβ) protects cardiomyocytes from doxorubicin-induced DNA double-strand breaks and transcriptome changes that are responsible for defective mitochondrial biogenesis and ROS formation. Furthermore, cardiomyocyte-specific deletion of Top2b protects mice from the development of doxorubicin-induced progressive heart failure, suggesting that doxorubicin-induced cardiotoxicity is mediated by topoisomerase-IIβ in cardiomyocytes.

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Figure 1: Time-dependent changes in the transcriptome after acute doxorubicin treatment.
Figure 2: Changes in mitochondrial function and structure after acute doxorubicin treatment, and in heart function after chronic doxorubicin treatment.

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Acknowledgements

We thank C.H. Ren for expert technical assistance and F.M. Lin and H. Dou for conducting studies on mitochondria DNA. W.C. Claycomb (Louisiana State University Health Science Center) provided HL-1 cells. This study is supported by the Cancer Prevention Research Institute of Texas and McNair Medical Institute (E.T.H.Y.), US National Institutes of Health grant CA102463 (to L.F.L.), the New Jersey Commission on Cancer Research Grant 06-2419-CCR-EO, US Department of Defense Idea Award W81XWH-07-1-0407 and Concept Award W81XWH06-1-0514 (to Y.L.L.).

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Authors and Affiliations

  1. Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

    Sui Zhang, Tasneem Bawa-Khalfe & Edward T H Yeh

  2. Texas Heart Institute at St. Luke's Episcopal Hospital, Houston, Texas, USA

    Xiaobing Liu, Long-Sheng Lu & Edward T H Yeh

  3. Department of Vascular Surgery, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Xiaobing Liu

  4. Department of Pharmacology, University of Medicine and Dentistry of New Jersey—Robert Wood Johnson Medical School, Piscataway, New Jersey, USA

    Yi Lisa Lyu & Leroy F Liu

Authors
  1. Sui Zhang
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  2. Xiaobing Liu
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  3. Tasneem Bawa-Khalfe
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  4. Long-Sheng Lu
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  5. Yi Lisa Lyu
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  6. Leroy F Liu
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  7. Edward T H Yeh
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Contributions

E.T.H.Y. and L.F.L. conceived the project. S.Z., X.L., T.B.-K., L.-S.L. and Y.L.L. performed experiments and data analysis. E.T.H.Y. and S.Z. wrote the manuscript with editorial input from L.F.L. and Y.L.L.

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Correspondence to Edward T H Yeh.

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Supplementary Figures 1–5 and Supplementary Tables 1 and 2 (PDF 896 kb)

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Zhang, S., Liu, X., Bawa-Khalfe, T. et al. Identification of the molecular basis of doxorubicin-induced cardiotoxicity. Nat Med 18, 1639–1642 (2012). https://doi.org/10.1038/nm.2919

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