Acute doxorubicin cardiotoxicity is associated with miR-146a-induced inhibition of the neuregulin-ErbB pathway.
Acute doxorubicin cardiotoxicity is associated with miR-146a-induced inhibition of the neuregulin-ErbB pathway.
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DOI：
10.1093/cvr/cvq148
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发表时间：
2010-09-01
影响因子：
10.8
通讯作者：
Kimura T
中科院分区：
文献类型：
--
作者：
Horie T;Ono K;Nishi H;Nagao K;Kinoshita M;Watanabe S;Kuwabara Y;Nakashima Y;Takanabe-Mori R;Nishi E;Hasegawa K;Kita T;Kimura T
据报道，当抗ErbB 2抗体曲妥珠单抗与化疗药物阿霉素（Dox）联合使用时，充血性心力衰竭（CHF）显著增加。本研究的目的是研究miRNAs在急性Dox诱导的心脏毒性中的作用。Neuregulin-1-ErbB信号传导对于维持成人心脏功能至关重要。我们发现Dox治疗后小鼠心脏中ErbB 4表达显著减少。由于蛋白酶体途径仅部分参与ErbB 4表达的降低，因此我们检测了微小RNA（miRs）参与ErbB 4表达的降低。miR-146 a在新生大鼠心肌细胞中被Dox上调。利用荧光素酶报告基因检测和miR-146 a的过表达，我们证实miR-146 a靶向ErbB 4 3′UTR。在Dox处理后，miR-146 a的过表达以及针对ErbB 4的siRNA的过表达诱导心肌细胞中的细胞死亡。在miR-146 a过表达的心肌细胞中重新表达ErbB 4改善了Dox诱导的细胞死亡。为了检测miR-146 a功能的丧失，我们构建了“诱饵”基因，这些基因在荧光素酶基因的3′UTR中具有miR-146 a的串联互补序列。当将miR-146 a“诱饵”基因引入心肌细胞时，ErbB 4表达上调，Dox诱导的细胞死亡减少。这些结果表明，miR-146 a在Dox治疗后的上调通过靶向ErbB 4参与了Dox诱导的急性心脏毒性。ErbB 2和ErbB 4信号传导的抑制可能是接受Dox和曲妥珠单抗联合治疗的患者患有CHF的原因之一。
A significant increase in congestive heart failure (CHF) was reported when the anti-ErbB2 antibody trastuzumab was used in combination with the chemotherapy drug doxorubicin (Dox). The aim of the present study was to investigate the role(s) of miRNAs in acute Dox-induced cardiotoxicity. Neuregulin-1-ErbB signalling is essential for maintaining adult cardiac function. We found a significant reduction in ErbB4 expression in the hearts of mice after Dox treatment. Because the proteasome pathway was only partially involved in the reduction of ErbB4 expression, we examined the involvement of microRNAs (miRs) in the reduction of ErbB4 expression. miR-146a was shown to be up-regulated by Dox in neonatal rat cardiac myocytes. Using a luciferase reporter assay and overexpression of miR-146a, we confirmed that miR-146a targets the ErbB4 3′UTR. After Dox treatment, overexpression of miR-146a, as well as that of siRNA against ErbB4, induced cell death in cardiomyocytes. Re-expression of ErbB4 in miR-146a-overexpressing cardiomyocytes ameliorated Dox-induced cell death. To examine the loss of miR-146a function, we constructed ‘decoy’ genes that had tandem complementary sequences for miR-146a in the 3′UTR of a luciferase gene. When miR-146a ‘decoy’ genes were introduced into cardiomyocytes, ErbB4 expression was up-regulated and Dox-induced cell death was reduced. These findings suggested that the up-regulation of miR-146a after Dox treatment is involved in acute Dox-induced cardiotoxicity by targeting ErbB4. Inhibition of both ErbB2 and ErbB4 signalling may be one of the reasons why those patients who receive concurrent therapy with Dox and trastuzumab suffer from CHF.
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影响因子：
3.5
作者：
Perry, Mark M.;Williams, Andrew E.;Lindsay, Mark A.
通讯作者：
Lindsay, Mark A.
DOI：
10.1073/pnas.122249299
发表时间：
2002-06-25
影响因子：
11.1
作者：
Özcelik, C;Erdmann, B;Garratt, AN
通讯作者：
Garratt, AN
影响因子：
11.2
作者：
Hurst DR;Edmonds MD;Scott GK;Benz CC;Vaidya KS;Welch DR
通讯作者：
Welch DR
影响因子：
37.8
作者：
Li, K;Sung, RYT;Ng, PC
通讯作者：
Ng, PC
影响因子：
5
作者：
Nagao, Kazuya;Ono, Koh;Kimura, Takeshi
通讯作者：
Kimura, Takeshi