Targeted disruption of p53 attenuates doxorubicin-induced cardiac toxicity in mice
Targeted disruption of p53 attenuates doxorubicin-induced cardiac toxicity in mice
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DOI：
10.1007/s11010-005-5905-8
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发表时间：
2005-05-01
影响因子：
4.3
通讯作者：
Hwang, PM
中科院分区：
文献类型：
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作者：
Shizukuda, Y;Matoba, S;Hwang, PM
化疗药物阿霉素 (Dox) 的使用受到剂量依赖性心脏毒性作用的限制。这些毒性背后的分子机制尚不完全清楚，但之前的结果表明 Dox 会诱导 p53 表达。由于 p53 是细胞出生和死亡的重要调节因子，我们假设靶向破坏 p53 基因将减弱 Dox 诱导的心脏毒性。为了测试这一点，将 6-8 周龄的雌性 C57BL 野生型 (WT) 或 p53 敲除 (p53 KO) 小鼠随机分配至生理盐水或通过腹膜内注射 20 mg/kg 的 Dox。使用高频（14 MHz）二维超声心动图对动物进行连续成像。通过缩短分数 (FS) 评估的左心室 (LV) 收缩功能测量表明，WT 小鼠早在注射 Dox 后 4 天就出现了下降，到注射 2 周后，左心室 (LV) 收缩功能较基线下降了 31 +/- 16% (P < 0.05)。相反，在 p53 KO 小鼠中，注射 Dox 后 2 周内 LV FS 没有变化。 Dox 治疗后 24 小时，WT 小鼠中通过 TUNEL 和连接酶反应测量的心肌细胞凋亡显着增加，但 p53 KO 小鼠中则没有。注射 Dox 后，p53 KO 小鼠的心肌谷胱甘肽和 Cu/Zn 超氧化物歧化酶水平保持不变，但 WT 动物则不然。这些观察结果表明，p53 介导的信号可能在 Dox 诱导的心脏毒性中发挥重要作用，并且它们可能调节 Dox 诱导的氧化应激。
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.