Activation of miR-34a-5p/Sirt1/p66shc pathway contributes to doxorubicin-induced cardiotoxicity.
Activation of miR-34a-5p/Sirt1/p66shc pathway contributes to doxorubicin-induced cardiotoxicity.
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miR-34a-5p/Sirt1/p66shc 通路的激活导致阿霉素诱导的心脏毒性
DOI：
10.1038/s41598-017-12192-y
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发表时间：
2017-09-19
影响因子：
4.6
通讯作者：
Shan ZX
中科院分区：
文献类型：
--
作者：
Zhu JN;Fu YH;Hu ZQ;Li WY;Tang CM;Fei HW;Yang H;Lin QX;Gou DM;Wu SL;Shan ZX
蒽环类药物引起心脏毒性的分子机制尚未完全阐明。Dox处理组大鼠心肌和血浆中的miRNAs表达异常。在Dox处理的大鼠的心肌和血浆中证实MicroRNA-34 a-5 p（miR-34 a-5 p）增加，但在接受Dox加DEX处理的大鼠中逆转。在9周和16周表阿霉素治疗后，弥漫性大B细胞淋巴瘤患者的血浆中也观察到人miR-34 a-5 p增加。在Dox诱导的大鼠心肌细胞H9 c2细胞中观察到miR-34 a-5 p的上调。miR-34 a-5 p可增加Bax的表达，但抑制Bcl-2的表达，并沿着caspase-3活性和线粒体电位的升高。MiR-34 a-5 p被证实在转录后调节Sirt 1的表达。miR-34 a-5 p可增强H9 c2细胞中p66 shc的表达，同时上调Bax和活化的caspase-3的表达，下调Bcl-2的表达。此外，Sirt 1的强表达可减轻Dox诱导的H9 c2细胞凋亡，抑制p66 shc、Bax、活化的caspase-3和miR-34 a-5 p的水平，并增强Bcl-2的表达。因此，miR-34 a-5 p通过靶向Sirt 1促进心肌细胞凋亡，miR-34 a-5 p/Sirt 1/p66 shc通路的激活参与了Dox诱导的心脏毒性，阻断该通路代表了蒽环类药物潜在的心脏保护作用。
The molecular mechanisms underlying anthracyclines-induced cardiotoxicity have not been well elucidated. MiRNAs were revealed dysregulated in the myocardium and plasma of rats received Dox treatment. MicroRNA-34a-5p (miR-34a-5p) was verified increased in the myocardium and plasma of Dox-treated rats, but was reversed in rats received Dox plus DEX treatments. Human miR-34a-5p was also observed increased in the plasma of patients with diffuse large B-cell lymphoma after 9- and 16-week epirubicin therapy. Up-regulation of miR-34a-5p was observed in Dox-induced rat cardiomyocyte H9c2 cells. MiR-34a-5p could augment Bax expression, but inhibited Bcl-2 expression, along with the increases of the activated caspase-3 and mitochondrial potentials in H9C2 cells. MiR-34a-5p was verified to modulate Sirt1 expression post-transcriptionally. In parallel to Sirt1 siRNA, miR-34a-5p could enhance p66shc expression, accompanied by increases of Bax and the activated caspase-3 and a decrease of Bcl-2 in H9c2 cells. Moreover, enforced expression of Sirt1 alleviated Dox-induced apoptosis of H9c2 cells, with suppressing levels of p66shc, Bax, the activated caspase-3 and miR-34a-5p, and enhancing Bcl-2 expression. Therefore, miR-34a-5p enhances cardiomyocyte apoptosis by targeting Sirt1, activation of miR-34a-5p/Sirt1/p66shc pathway contributes to Dox-induced cardiotoxicity, and blockage of this pathway represents a potential cardioprotective effect against anthracyclines.
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影响因子：
4.3
作者：
Fu, Jun;Peng, Cike;Wei, Xuetao
通讯作者：
Wei, Xuetao
影响因子：
20.3
作者：
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通讯作者：
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影响因子：
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作者：
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影响因子：
10.8
作者：
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通讯作者：
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影响因子：
5
作者：
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通讯作者：
Pani, Giovambattista