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JCI:阿霉素通过介导线粒体中铁的积累诱发心脏毒性

来源:生物谷 2014-01-05 20:00

2014年1月5日讯 /生物谷BIOON/--阿霉素(多柔比星)是一种广泛使用的化疗方案中的一个组成成分,但是,使用多柔比星会引发严重的心脏毒性。

目前还不清楚到底阿霉素如何促发心脏毒性,但已有研究提示,多柔比星相关心肌病的发展,是活性氧( ROS)的产生和铁积累的结果。

发表在Journal of Clinical Investigation杂志上的一则新研究中,西北大学Hossein Ardehali和同事们确定了阿霉素在心肌细胞线粒体内积累,这种积累会促进线粒体ROS的产生和铁的积累。

在阿霉素相关的心脏毒性小鼠模型中,线粒体铁转运蛋白质过表达后能减少线粒体的铁、活性氧的积累,并保护动物免于多柔比星诱发的心肌疾病。

动物用右丙亚胺(其能衰减阿霉素引起的心脏毒性)治疗,能降低线粒体铁积累水平和逆转阿霉素引起的心脏损伤。

此外,利用阿霉素治疗的患者心脏样本发现心肌疾病(Cardiomyopathies)患者相比与无心脏并发症患者,有更高水平的线粒体铁积累。这些数据表明,限制线粒体的铁蓄积能潜在限制阿霉素相关的心脏毒性。(生物谷Bioon.com)

 

Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation

Yoshihiko Ichikawa,et al.

Doxorubicin is an effective anticancer drug with known cardiotoxic side effects. It has been hypothesized that doxorubicin-dependent cardiotoxicity occurs through ROS production and possibly cellular iron accumulation. Here, we found that cardiotoxicity develops through the preferential accumulation of iron inside the mitochondria following doxorubicin treatment. In isolated cardiomyocytes, doxorubicin became concentrated in the mitochondria and increased both mitochondrial iron and cellular ROS levels. Overexpression of ABCB8, a mitochondrial protein that facilitates iron export, in vitro and in the hearts of transgenic mice decreased mitochondrial iron and cellular ROS and protected against doxorubicin-induced cardiomyopathy. Dexrazoxane, a drug that attenuates doxorubicin-induced cardiotoxicity, decreased mitochondrial iron levels and reversed doxorubicin-induced cardiac damage. Finally, hearts from patients with doxorubicin-induced cardiomyopathy had markedly higher mitochondrial iron levels than hearts from patients with other types of cardiomyopathies or normal cardiac function. These results suggest that the cardiotoxic effects of doxorubicin develop from mitochondrial iron accumulation and that reducing mitochondrial iron levels protects against doxorubicin-induced cardiomyopathy.

 

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