Doxorubicin Inactivates Myocardial Cytochrome c Oxidase in Rats: Cardioprotection by Mito-Q
Doxorubicin Inactivates Myocardial Cytochrome c Oxidase in Rats: Cardioprotection by Mito-Q
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DOI：
10.1016/j.bpj.2008.10.042
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发表时间：
2009-02-18
影响因子：
3.4
通讯作者：
Kalyanaraman, B.
中科院分区：
文献类型：
--
作者：
Chandran, Karunakaran;Aggarwal, Deepika;Kalyanaraman, B.
阿霉素（DOX）用于治疗各种癌症。然而，其临床应用受到其剂量限制性心肌病的限制。DOX诱导心肌病的确切机制仍不清楚。目的是研究DOX诱导的心肌病的分子机制和线粒体醌（Mito-Q）的心脏保护作用，线粒体醌是一种三苯基膦共轭的辅酶Q类似物，使用大鼠模型。用DOX、Mito-Q和DOX加Mito-Q处理大鼠12周。用二维超声心动图测量的左心室功能在DOX治疗的大鼠中降低，但在Mito-Q加DOX治疗期间保持不变。使用低温离体电子顺磁共振（EPR），血红素信号的时间依赖性减少检测到从大鼠心脏组织中分离与累积剂量的DOX。DOX减弱了细胞色素c氧化酶（CcO）-Fe（III）血红素a（3）和Cu-B之间交换相互作用的EPR信号特征。DOX和Mito-Q一起恢复了心脏组织中的这些EPR信号和CcO活性。DOX对CcO亚基II和Va的稳定表达有明显的调节作用，对CcO亚基I的表达有轻微的抑制作用。Mito-Q恢复了DOX处理大鼠中CcO亚基II和Va的表达。这些结果提示Mito-O在涉及CcO的DOX诱导的心肌病中的一种新的心脏保护机制。
Doxorubicin (DOX) is used for treating various cancers. Its clinical use is, however, limited by its dose-limiting cardiomyopathy. The exact mechanism of DOX-induced cardiomyopathy still remains unknown. The goals were to investigate the molecular mechanism of DOX-induced cardionnyopathy and cardioprotection by mitoquinone (Mito-Q), a triphenylphosphonium-conjugated analog of coenzyme Q, using a rat model. Rats were treated with DOX, Mito-Q, and DOX plus Mito-Q for 12 weeks. The left ventricular function as measured by two-dimensional echocardiography decreased in DOX-treated rats but was preserved during Mito-Q plus DOX treatment. Using low-temperature ex vivo electron paramagnetic resonance (EPR), a time-dependent decrease in heme signal was detected in heart tissues isolated from rats administered with a cumulative dose of DOX. DOX attenuated the EPR signals characteristic of the exchange interaction between cytochrome c oxidase (CcO)-Fe(III) heme a(3) and Cu-B. DOX and Mito-Q together restored these EPR signals and the CcO activity in heart tissues. DOX strongly clownregulated the stable expression of the CcO subunits II and Va and had a slight inhibitory effect on CcO subunit I gene expression. Mito-Q restored CcO subunit II and Va expressions in DOX-treated rats. These results suggest a novel cardioprotection mechanism by Mito-O during DOX-induced cardiomyopathy involving CcO.