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首页> 外文期刊>Canadian Journal of Physiology and Pharmacology >Diminished molecular response to doxorubicin and loss of cardioprotective effect of dexrazoxane in Egr-1 deficient female mice.
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Diminished molecular response to doxorubicin and loss of cardioprotective effect of dexrazoxane in Egr-1 deficient female mice.

机译：Egr-1缺乏的雌性小鼠对阿霉素的分子反应减弱，而右雷佐生的心脏保护作用丧失。

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Doxorubicin (DOX) and VP16 are DNA topoisomerase II inhibitors yet only DOX induces an irreversible cardiotoxicity, likely through DOX-induced oxidative stress. Egr-1 is overexpressed after many stimuli that increase oxidative stress in vitro and after DOX-injection into adult mice in vivo. To investigate Egr-1 function in the heart, we compared the molecular and histological responses of wild type (+/+) and Egr-1 deficient (-/-) female mice to saline, DOX, VP16, the cardioprotectant dexrazoxane (DZR), or DOX+DZR injection. DOX, and to a lesser extent VP16, induced characteristic increases in cardiac muscle and non-muscle genes typical of cardiac damage in +/+ mice, whereas only beta-MHC and Sp1 were increased in -/- mice. DZR-alone treated +/+ mice showed increased cardiomyocyte transnuclear width without a change to the heart to body weight (HW/BW) ratio. However, DZR-alone treated -/- mice had an increased HW/BW, increased cardiomyocyte transnuclear width, and gene expression changes similar to DOX-injected +/+ mice. DZR pre-injection alleviated DOX-induced gene changes in +/+ mice; in DZR+DOX injected -/- mice the increases in cardiac and non-muscle gene expression were equal to, or exceeded that, detected after DOX-alone or DZR-alone injections. We conclude that Egr-1 is required for DOX-induced molecular changes and for DZR-mediated cardioprotection.
机译：阿霉素（DOX）和VP16是DNA拓扑异构酶II抑制剂，但只有DOX可能通过DOX诱导的氧化应激诱导不可逆的心脏毒性。在多次刺激后会增加Egr-1的表达，这些刺激会在体外增加氧化应激，在体内将DOX注射入成年小鼠后。为了研究心脏中的Egr-1功能，我们比较了野生型（+ / +）和Egr-1缺陷型（-/-）雌性小鼠对盐水，DOX，VP16，心脏保护剂右雷佐生（DZR）的分子和组织学反应或DOX + DZR注入。在+ / +小鼠中，DOX和较小程度的VP16诱导的心肌和非肌肉基因的典型特征是心肌损伤，而在-/-小鼠中，只有beta-MHC和Sp1升高。单独使用DZR处理的+ / +小鼠显示心肌细胞的跨核宽度增加，而心与体重（HW / BW）之比没有变化。但是，仅DZR处理的-/-小鼠的HW / BW增加，心肌细胞的跨核宽度增加，并且基因表达的变化类似于注入DOX的+ / +小鼠。 DZR预注射减轻了DOX诱导的+/-小鼠的基因变化;在注射DZR + DOX的小鼠中，心脏和非肌肉基因表达的增加等于或超过仅注射DOX或单独注射DZR后检测到的增加。我们得出结论，Egr-1是DOX诱导的分子变化和DZR介导的心脏保护所必需的。

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