Activation of miR-34a-5p/Sirt1/p66shc pathway contributes to doxorubicin-induced cardiotoxicity

作者：Zhu, Jie-Ning; Fu, Yong-Heng; Hu, Zhi-qin; Li, Wen-Yu; Tang, Chun-Mei; Fei, Hong-Wen; Yang, Hui; Lin, Qiu-xiong; Gou, De-Ming; Wu, Shu-Lin; Shan, Zhi-Xin^*

来源：Scientific Reports, 2017, 7(1): 11879.

DOI：10.1038/s41598-017-12192-y

• ANTHRACYCLINE CARDIOTOXICITY
• OXIDATIVE STRESS
• LIFE-SPAN
• CARDIOMYOCYTE HYPERTROPHY
• MYOCARDIAL-INFARCTION
• CELL-DEATH
• APOPTOSIS
• DEXRAZOXANE
• EXPRESSION
• MICRORNAS

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.

• 出版日期2017-9-19
• 单位广东省心血管病研究所; 广东省人民医院; 深圳大学