Chandran Karunakaran, Aggarwal Deepika, Migrino Raymond Q, Joseph Joy, McAllister Donna, Konorev Eugene A, Antholine William E, Zielonka Jacek, Srinivasan Satish, Avadhani Narayan G, Kalyanaraman B
Department of Biophysics and Free Radical Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
Biophys J. 2009 Feb 18;96(4):1388-98. doi: 10.1016/j.bpj.2008.10.042.
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 cardiomyopathy 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 a3 and CuB. DOX and Mito-Q together restored these EPR signals and the CcO activity in heart tissues. DOX strongly downregulated 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-Q during DOX-induced cardiomyopathy involving CcO.
阿霉素（DOX）用于治疗多种癌症。然而，其临床应用受到剂量限制性心肌病的限制。DOX诱导的心肌病的确切机制仍然未知。目的是使用大鼠模型研究DOX诱导的心肌病的分子机制以及线粒体醌（Mito-Q，一种辅酶Q的三苯基鏻共轭类似物）的心脏保护作用。大鼠分别接受DOX、Mito-Q以及DOX加Mito-Q治疗12周。二维超声心动图测量显示，DOX治疗的大鼠左心室功能下降，但在Mito-Q加DOX治疗期间得以保留。使用低温离体电子顺磁共振（EPR），在给予累积剂量DOX的大鼠分离的心脏组织中检测到血红素信号随时间下降。DOX减弱了细胞色素c氧化酶（CcO）-Fe（III）血红素a3与CuB之间交换相互作用的特征性EPR信号。DOX和Mito-Q共同恢复了心脏组织中的这些EPR信号和CcO活性。DOX强烈下调CcO亚基II和Va的稳定表达，并对CcO亚基I基因表达有轻微抑制作用。Mito-Q恢复了DOX治疗大鼠中CcO亚基II和Va的表达。这些结果表明，在DOX诱导的涉及CcO的心肌病中，Mito-Q具有一种新的心脏保护机制。
