Zhu Wuqiang, Soonpaa Mark H, Chen Hanying, Shen Weihua, Payne R Mark, Liechty Edward A, Caldwell Randall L, Shou Weinian, Field Loren J
Riley Heart Research Center, Herman B Wells Center for Pediatric Research, Indianapolis, IN 46202-5225, USA.
Circulation. 2009 Jan 6;119(1):99-106. doi: 10.1161/CIRCULATIONAHA.108.799700. Epub 2008 Dec 22.
Doxorubicin is used to treat childhood and adult cancer. Doxorubicin treatment is associated with both acute and chronic cardiotoxicity. The cardiotoxic effects of doxorubicin are cumulative, which limits its chemotherapeutic dose. Free radical generation and p53-dependent apoptosis are thought to contribute to doxorubicin-induced cardiotoxicity.
Adult transgenic (MHC-CB7) mice expressing cardiomyocyte-restricted dominant-interfering p53 and their nontransgenic littermates were treated with doxorubicin (20 mg/kg cumulative dose). Nontransgenic mice exhibited reduced left ventricular systolic function (predoxorubicin fractional shortening [FS] 61+/-2%, postdoxorubicin FS 45+/-2%, mean+/-SEM, P<0.008), reduced cardiac mass, and high levels of cardiomyocyte apoptosis 7 days after the initiation of doxorubicin treatment. In contrast, doxorubicin-treated MHC-CB7 mice exhibited normal left ventricular systolic function (predoxorubicin FS 63+/-2%, postdoxorubicin FS 60+/-2%, P>0.008), normal cardiac mass, and low levels of cardiomyocyte apoptosis. Western blot analyses indicated that mTOR (mammalian target of rapamycin) signaling was inhibited in doxorubicin-treated nontransgenic mice but not in doxorubicin-treated MHC-CB7 mice. Accordingly, transgenic mice with cardiomyocyte-restricted, constitutively active mTOR expression (MHC-mTORca) were studied. Left ventricular systolic function (predoxorubicin FS 64+/-2%, postdoxorubicin FS 60+/-3%, P>0.008) and cardiac mass were normal in doxorubicin-treated MHC-mTORca mice, despite levels of cardiomyocyte apoptosis similar to those seen in doxorubicin-treated nontransgenic mice.
These data suggest that doxorubicin 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 doxorubicin cardiotoxicity.
阿霉素用于治疗儿童和成人癌症。阿霉素治疗与急性和慢性心脏毒性均相关。阿霉素的心脏毒性作用具有累积性，这限制了其化疗剂量。自由基生成和p53依赖性细胞凋亡被认为与阿霉素诱导的心脏毒性有关。
用阿霉素（累积剂量20mg/kg）处理表达心肌细胞限制性显性干扰p53的成年转基因（MHC-CB7）小鼠及其非转基因同窝仔鼠。非转基因小鼠在阿霉素治疗开始7天后出现左心室收缩功能降低（阿霉素治疗前缩短分数[FS]为61±2%，阿霉素治疗后FS为45±2%，平均值±标准误，P<0.008）、心脏质量减轻以及心肌细胞凋亡水平升高。相比之下，经阿霉素处理的MHC-CB7小鼠左心室收缩功能正常（阿霉素治疗前FS为63±2%，阿霉素治疗后FS为60±2%，P>0.008）、心脏质量正常且心肌细胞凋亡水平较低。蛋白质免疫印迹分析表明，在经阿霉素处理的非转基因小鼠中mTOR（雷帕霉素靶蛋白）信号通路受到抑制，而在经阿霉素处理的MHC-CB7小鼠中未受抑制。因此，研究了具有心肌细胞限制性、组成型活性mTOR表达的转基因小鼠（MHC-mTORca）。尽管经阿霉素处理的MHC-mTORca小鼠心肌细胞凋亡水平与经阿霉素处理的非转基因小鼠相似，但其左心室收缩功能（阿霉素治疗前FS为64±2%，阿霉素治疗后FS为60±3%，P>0.008）和心脏质量正常。
这些数据表明，阿霉素治疗通过p53依赖性抑制mTOR信号通路诱导急性心脏功能障碍并减轻心脏质量，并且心肌质量的减少而非心肌细胞凋亡是急性阿霉素心脏毒性的主要原因。
