Thrombopoietin protects against in vitro and in vivo cardiotoxicity induced by doxorubicin
Thrombopoietin protects against in vitro and in vivo cardiotoxicity induced by doxorubicin
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DOI：
10.1161/circulationaha.105.560250
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发表时间：
2006-05-09
期刊：
影响因子：
37.8
通讯作者：
Ng, PC
中科院分区：
文献类型：
--
作者：
Li, K;Sung, RYT;Ng, PC
背景-阿霉素(DOX)是一种重要的抗肿瘤药物。然而，与之相关的心脏毒性，可能是由活性氧的产生所介导的，仍然是一个重要的和剂量受限的临床问题。我们的假设是，造血/巨核细胞生长因子血小板生成素(TPO)对DOX诱导的心脏毒性具有保护作用，可能涉及对心肌细胞的抗凋亡机制。方法和结果：对H9C2细胞系和原代、新生大鼠心室自发搏动细胞进行了体外研究，并对DOX诱导的急性心肌病小鼠进行了体内研究。我们的结果表明，TPO可显著提高DOX损伤的H9C2细胞的存活率和新生心肌细胞的搏动频率，其作用与临床批准的心脏保护剂右旋氮杂环己烷相似。通过检测Annexin V、活性caspase-3和线粒体膜电位，TPO可改善DOX诱导的H9C2细胞的凋亡。在小鼠模型中，给予TPO(12.5 mg/kg ip，隔日3天)可显著降低DOX(20 mg/kg)所致的心脏毒性，包括低血细胞计数、心肌细胞损伤(细胞凋亡、空泡化和肌原纤维丢失)和动物死亡率。利用多普勒超声心动图，我们观察到与单用DOX组相比，TPO组动物的心率、短轴缩短率和心输出量都有所增加。结论--这些数据首次证明TPO对DOX所致的心脏损伤具有保护作用。我们建议进一步探索一种综合方案，将TPO与其他方案相结合，用于治疗DOX引起的心脏毒性和其他形式的心肌病。
Background - Doxorubicin (DOX) is an important antineoplastic agent. However, the associated cardiotoxicity, possibly mediated by the production of reactive oxygen species, has remained a significant and dose-limiting clinical problem. Our hypothesis is that the hematopoietic/megakaryocytopoietic growth factor thrombopoietin (TPO) protects against DOX-induced cardiotoxicity and might involve antiapoptotic mechanism exerted on cardiomyocytes.Methods and Results - In vitro investigations on H9C2 cell line and spontaneously beating cells of primary, neonatal rat ventricle, as well as an in vivo study in a mouse model of DOX-induced acute cardiomyopathy, were performed. Our results showed that pretreatment with TPO significantly increased viability of DOX-injured H9C2 cells and beating rates of neonatal myocytes, with effects similar to those of dexrazoxane, a clinically approved cardiac protective agent. TPO ameliorated DOX-induced apoptosis of H9C2 cells as demonstrated by assays of annexin V, active caspase-3, and mitochondrial membrane potential. In the mouse model, administration of TPO (12.5 mu g/kg IP for 3 alternate days) significantly reduced DOX-induced (20 mg/kg) cardiotoxicity, including low blood cell count, cardiomyocyte lesions ( apoptosis, vacuolization, and myofibrillar loss), and animal mortality. Using Doppler echocardiography, we observed increased heart rate, fractional shortening, and cardiac output in animals pretreated with TPO compared with those receiving DOX alone.Conclusions - These data have provided the first evidence that TPO is a protective agent against DOX-induced cardiac injury. We propose to further explore an integrated program, incorporating TPO with other protocols, for treatment of DOX-induced cardiotoxicity and other forms of cardiomyopathy.