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Targeted disruption of p53 attenuates doxorubicin-induced cardiac toxicity in mice

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Abstract

Use of the chemotherapeutic agent doxorubicin (Dox) is limited by dose-dependent cardiotoxic effects. The molecular mechanism underlying these toxicities are incompletely understood, but previous results have demonstrated that Dox induces p53 expression. Because p53 is an important regulator of the cell birth and death we hypothesized that targeted disruption of the p53 gene would attenuate Dox-induced cardiotoxicity. To test this, female 6–8 wk old C57BL wild-type (WT) or p53 knockout (p53 KO) mice were randomized to either saline or Dox 20 mg/kg via intraperitoneal injection. Animals were serially imaged with high-frequency (14 MHz) two-dimensional echocardiography. Measurements of left ventricle (LV) systolic function as assessed by fractional shortening (FS) demonstrated a decline in WT mice as early as 4 days after Dox injection and by 2 wk demonstrated a reduction of 31± 16% (P < 0.05) from the baseline. In contrast, in p53 KO mice, LV FS was unchanged over the 2 wk period following Dox injection. Apoptosis of cardiac myocytes as measured by the TUNEL and ligase reactions were significantly increased at 24 h after Dox treatment in WT mice but not in p53 KO mice. After Dox injection, levels of myocardial glutathione and Cu/Zn superoxide dismutase were preserved in p53 KO mice, but not in WT animals. These observations suggest that p53 mediated signals are likely to play a significant role in Dox-induced cardiac toxicity and that they may modulate Dox-induced oxidative stress.

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Authors and Affiliations

  1. Cardiovascular Branch, National Heart Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA

    Yukitaka Shizukuda MD, PhD, Satoaki Matoba, Omar Y. Mian, Tammy Nguyen & Paul M. Hwang

  2. Cardiovascular Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Building 10-CRC, Room 6-3142, 10 Center Drive, MSC-1454, Bethesda, MD, 20892

    Yukitaka Shizukuda MD, PhD

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  1. Yukitaka Shizukuda MD, PhD
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  2. Satoaki Matoba
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  3. Omar Y. Mian
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  4. Tammy Nguyen
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Correspondence to Yukitaka Shizukuda MD, PhD.

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These two authors equally contributed to this study.

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Shizukuda, Y., Matoba, S., Mian, O.Y. et al. Targeted disruption of p53 attenuates doxorubicin-induced cardiac toxicity in mice. Mol Cell Biochem 273, 25–32 (2005). https://doi.org/10.1007/s11010-005-5905-8

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  • DOI: https://doi.org/10.1007/s11010-005-5905-8

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