Acute doxorubicin cardiotoxicity is associated with p53-induced inhibition of the mammalian target of rapamycin pathway.
Acute doxorubicin cardiotoxicity is associated with p53-induced inhibition of the mammalian target of rapamycin pathway.
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DOI：
10.1161/circulationaha.108.799700
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发表时间：
2009-01-06
期刊：
影响因子：
37.8
通讯作者：
Field, Loren J.
中科院分区：
文献类型：
--
作者：
Zhu, Wuqiang;Soonpaa, Mark H.;Chen, Hanying;Shen, Weihua;Payne, R. Mark;Liechty, Edward A.;Caldwell, Randall L.;Shou, Weinian;Field, Loren J.
阿霉素(DOX)用于治疗儿童和成人癌症。DOX治疗与急性和慢性心脏毒性有关。DOX的心脏毒性作用是累积的，限制了其化疗剂量。自由基生成和P53依赖的细胞凋亡被认为与DOX诱导的心脏毒性有关。成年转基因(MHC-CB7)表达心肌细胞限制性显性干扰p53的小鼠及其非转基因小鼠(非TXG)给予DOX(20 mg/kg累积剂量)治疗。非血栓心绞痛小鼠在用药7天后表现出左心收缩功能降低(DOX治疗前FS=61±2%，DOX治疗后FS=45±2%，平均+/-扫描电子显微镜，p<；0.008)，心肌质量减少，心肌细胞凋亡水平升高。相比之下，DOX治疗的MHC-CB7小鼠表现出正常的左心收缩功能(DOX前FS=63±2%，DOX后FS=60±2%，p>；0.008)，心脏质量正常，心肌细胞凋亡水平较低。Western印迹分析表明，在DOX处理的非TXG小鼠中，mTOR信号转导受到抑制，但在DOX处理的MHC-CB7小鼠中没有。因此，我们研究了心肌细胞限制性成分活性mTOR表达转基因小鼠(MHC-mTORca)。DOX组小鼠左心收缩功能(DOX前FS=+/-2%，DOX后FS 60+/-3%，p>；0.008)和心脏质量正常，尽管心肌细胞凋亡水平与DOX非TXG组相似。这些数据表明，DOX治疗通过抑制p53依赖的mTOR信号通路而导致急性心功能不全和心脏质量减少，而心肌质量损失而不是心肌细胞凋亡是导致急性DOX心脏毒性的主要因素。
Doxorubicin (DOX) is used to treat childhood and adult cancer. DOX treatment is associated with both acute and chronic cardiotoxicity. The cardiotoxic effects of DOX are cumulative, limiting its chemotherapeutic dose. Free radical generation and p53-dependent apoptosis are thought to contribute to DOX-induced cardiotoxicity. Adult transgenic (MHC-CB7) mice expressing cardiomyocyte-restricted dominant-interfering p53 and their non-transgenic (NON-TXG) littermates were treated with DOX (20 mg/kg cumulative dose). NON-TXG mice exhibited reduced left ventricular (LV) systolic function (pre-DOX Fractional Shortening, FS, = 61 ± 2%, post-DOX FS = 45 ± 2%, mean +/- SEM, p<0.008), reduced cardiac mass, and high levels of cardiomyocyte apoptosis 7 days after the initiation of DOX treatment. In contrast, DOX-treated MHC-CB7 mice exhibited normal LV systolic function (pre-DOX FS = 63 ± 2%, post-DOX FS = 60 ± 2%, p>0.008), normal cardiac mass, and low levels of cardiomyocyte apoptosis. Western blot analyses indicated mTOR signaling was inhibited in DOX-treated NON-TXG mice, but not in DOX-treated MHC-CB7 mice. Accordingly, transgenic mice with cardiomyocyte-restricted constitutively active mTOR expression (MHC-mTORca) were studied. LV systolic function (pre-DOX FS = 64 +/- 2%, post-DOX FS 60 +/- 3%, p>0.008) and cardiac mass were normal in DOX-treated MHC-mTORca mice, despite similar levels of cardiomyocyte apoptosis as seen in DOX-treated NON-TXG mice. These data suggest that DOX treatment induces acute cardiac dysfunction and reduces cardiac mass via p53-dependent inhibition of mTOR signaling, and that loss of myocardial mass, and not cardiomyocyte apoptosis, is the major contributor to acute DOX cardiotoxicity.