Brain-derived neurotrophic factor attenuates doxorubicin-induced cardiac dysfunction through activating Akt signalling in rats.
Brain-derived neurotrophic factor attenuates doxorubicin-induced cardiac dysfunction through activating Akt signalling in rats.
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脑源性神经营养因子通过激活 Akt 信号传导减轻大鼠阿霉素诱导的心功能障碍
DOI：
10.1111/jcmm.13012
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发表时间：
2017-04
影响因子：
5.3
通讯作者：
Li Y
中科院分区：
文献类型：
--
作者：
Hang P;Zhao J;Sun L;Li M;Han Y;Du Z;Li Y
阿霉素（Dox）因其心脏毒性的不良反应而限制其临床应用。先前的研究表明脑源性神经营养因子（BDNF）具有心脏保护作用。我们假设 BDNF 可以预防 Dox 引起的心脏毒性。在存在或不存在重组 BDNF（0.4 μg/kg，静脉注射）的情况下，给 Sprague Dawley 大鼠注射 Dox（2.5 mg/kg，每周 3 次，腹腔注射），持续 2 周。 H9c2 细胞用 Dox (1 μM) 和/或 BDNF (400 ng/ml) 处理 24 小时。在体内和体外检查了 BDNF 对 Dox 诱导的心脏损伤的功能作用。在 Dox 治疗的大鼠心室中 BDNF 的蛋白水平降低，而 BDNF 及其受体原肌球蛋白相关激酶 B (TrkB) 在 BDNF 给药后显着上调。脑源性神经营养因子显着抑制 Dox 诱导的大鼠心肌细胞凋亡、氧化应激和心功能障碍。同时，BDNF 增加了 Dox 处理的 H9c2 细胞的细胞活力，抑制细胞凋亡和 DNA 损伤。对潜在机制的研究表明，BDNF 激活 Akt 并保留哺乳动物雷帕霉素和 Bad 靶标的磷酸化，而不影响 p38 丝裂原激活蛋白激酶和细胞外调节蛋白激酶途径。此外，BDNF 的有益作用被 BDNF 清除剂 TrkB-Fc 或 Akt 抑制剂消除。总之，我们的研究结果揭示了 BDNF 通过激活 Akt 信号传导对 Dox 诱导的心脏毒性具有有效的保护作用，这可能有助于在癌症治疗中安全使用 Dox。
The clinical application of doxorubicin (Dox) is limited by its adverse effect of cardiotoxicity. Previous studies have suggested the cardioprotective effect of brain‐derived neurotrophic factor (BDNF). We hypothesize that BDNF could protect against Dox‐induced cardiotoxicity. Sprague Dawley rats were injected with Dox (2.5 mg/kg, 3 times/week, i.p.), in the presence or absence of recombinant BDNF (0.4 μg/kg, i.v.) for 2 weeks. H9c2 cells were treated with Dox (1 μM) and/or BDNF (400 ng/ml) for 24 hrs. Functional roles of BDNF against Dox‐induced cardiac injury were examined both in vivo and in vitro. Protein level of BDNF was reduced in Dox‐treated rat ventricles, whereas BDNF and its receptor tropomyosin‐related kinase B (TrkB) were markedly up‐regulated after BDNF administration. Brain‐derived neurotrophic factor significantly inhibited Dox‐induced cardiomyocyte apoptosis, oxidative stress and cardiac dysfunction in rats. Meanwhile, BDNF increased cell viability, inhibited apoptosis and DNA damage of Dox‐treated H9c2 cells. Investigations of the underlying mechanisms revealed that BDNF activated Akt and preserved phosphorylation of mammalian target of rapamycin and Bad without affecting p38 mitogen‐activated protein kinase and extracellular regulated protein kinase pathways. Furthermore, the beneficial effect of BDNF was abolished by BDNF scavenger TrkB‐Fc or Akt inhibitor. In conclusion, our findings reveal a potent protective role of BDNF against Dox‐induced cardiotoxicity by activating Akt signalling, which may facilitate the safe use of Dox in cancer treatment.