Overexpression of Nd1, a novel Kelch family protein, in the heart of transgenic mice protects against doxorubicin-induced cardiomyopathy
Overexpression of Nd1, a novel Kelch family protein, in the heart of transgenic mice protects against doxorubicin-induced cardiomyopathy
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DOI：
10.1007/s11248-006-9010-x
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发表时间：
2006-10-01
影响因子：
3
通讯作者：
Hatano, Masahiko
中科院分区：
文献类型：
--
作者：
Matsudo, Yuji;Takamori, Yasuyuki;Hatano, Masahiko
阿霉素是可用于癌症化疗的最有效的药物之一。然而，由于阿霉素对心肌细胞的严重副作用，其临床应用受到了极大的限制。由于ND1-L是一种新的肌动蛋白结合蛋白，在成年小鼠心脏中表达最丰富，因此我们研究了ND1-L在阿霉素诱导的心肌病中的作用。每隔3天给成年小鼠注射阿霉素(5 mg/kg×4次)，大约50%的注射小鼠在第一次注射后4周内死亡。第一次注射后3周内，ND1-L基因在心脏中的表达下降，大量心肌细胞死亡。转基因小鼠心脏过表达ND1-L基因可保护心肌细胞免受阿霉素诱导的细胞凋亡，提高阿霉素注射后的存活率。此外，在过表达ND1-L的培养细胞中观察到ERK1/2的激活。因此，ND1-L在保护心脏免受阿霉素引起的心肌病中起着关键作用。
Doxorubicin is one of the most effective drugs available for cancer chemotherapy. However, the clinical use of doxorubicin has been greatly limited because of severe side effects on cardiomyocytes. Since Nd1-L, a novel actin-binding protein, is expressed most abundantly in the heart of adult mice, we examined a role of Nd1-L in doxorubicin-induced cardiomyopathy. When doxorubicin (5 mg/kg x 4 times) was injected into adult mice at a 3-day-interval, approximately 50% of injected mice died within 4 weeks of the first injection. Nd1-L mRNA expression in the heart decreased within 3 weeks after the first injection and many cardiomyocytes of injected mice died by apoptosis. Overexpression of Nd1-L in the heart of transgenic mice protected the cardiomyocytes from apoptosis and improved survival rate after doxorubicin injection. Furthermore, activation of Erk1/2 was observed in cultured cells overexpressing Nd1-L. Thus, Nd1-L plays a critical role in protecting the heart from doxorubicin-induced cardiomyopathy.