Cardioprotective effects of fibroblast growth factor 21 against doxorubicin-induced toxicity via the SIRT1/LKB1/AMPK pathway.
Cardioprotective effects of fibroblast growth factor 21 against doxorubicin-induced toxicity via the SIRT1/LKB1/AMPK pathway.
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成纤维细胞生长因子 21 通过 SIRT1/LKB1/AMPK 途径对抗阿霉素诱导的毒性的心脏保护作用
DOI：
10.1038/cddis.2017.410
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发表时间：
2017-08-24
影响因子：
9
通讯作者：
Gu J
中科院分区：
文献类型：
--
作者：
Wang S;Wang Y;Zhang Z;Liu Q;Gu J
多柔比星（DOX）是一种高效的蒽环类抗生素，但其心脏毒性限制了其广泛应用。成纤维细胞生长因子21（Fibroblast growth factor 21，FGF 21）作为糖脂代谢的调节因子，近年来被证实具有心脏保护作用。本研究的目的是研究FGF 21对DOX诱导的心肌病可能的保护作用。我们在H9 c2细胞、成年小鼠心肌细胞和129 S1/SyImJ小鼠中初步建立了DOX诱导的心脏毒性模型，该模型清楚地显示了伴随炎症、氧化应激和凋亡损伤的心功能不全和心肌胶原积聚。FGF 21治疗可明显减轻DOX引起的心功能不全和病理改变。通过IKK/IκBα/核因子-κB通路下调炎症因子（肿瘤坏死因子-α和白细胞介素-6）表达，显示其有效的抗炎活性。FGF 21的抗氧化应激活性通过调节核转录因子红细胞2相关因子2的转录减少活性氧的产生来实现。其抗凋亡活性通过TUNEL阳性细胞和DNA片段的数量减少沿着Bax/Bcl-2表达比率降低来显示。在进一步的机制研究中，FGF 21增强sirtuin 1（SIRT 1）与肝激酶B1（LKB 1）的结合，然后降低LKB 1乙酰化，随后诱导AMP活化蛋白激酶（AMPK）活化，从而改善心脏炎症，氧化应激和细胞凋亡。这些改变被SIRT 1 RNAi显著抑制。本研究首次证明，FGF 21通过SIRT 1/LKB 1/AMPK信号通路抑制氧化应激、炎症和凋亡，明显预防了DOX诱导的心脏毒性。
Doxorubicin (DOX) is a highly effective antineoplastic anthracycline drug; however, the adverse effect of the cardiotoxicity has limited its widespread application. Fibroblast growth factor 21 (FGF21), as a well-known regulator of glucose and lipid metabolism, was recently shown to exert cardioprotective effects. The aim of this study was to investigate the possible protective effects of FGF21 against DOX-induced cardiomyopathy. We preliminarily established DOX-induced cardiotoxicity models in H9c2 cells, adult mouse cardiomyocytes, and 129S1/SyImJ mice, which clearly showed cardiac dysfunction and myocardial collagen accumulation accompanying by inflammatory, oxidative stress, and apoptotic damage. Treatment with FGF21 obviously attenuated the DOX-induced cardiac dysfunction and pathological changes. Its effective anti-inflammatory activity was revealed by downregulation of inflammatory factors (tumor necrosis factor-α and interleukin-6) via the IKK/IκBα/nuclear factor-κB pathway. The anti-oxidative stress activity of FGF21 was achieved via reduced generation of reactive oxygen species through regulation of nuclear transcription factor erythroid 2-related factor 2 transcription. Its anti-apoptotic activity was shown by reductions in the number of TUNEL-positive cells and DNA fragments along with a decreased ratio of Bax/Bcl-2 expression. In a further mechanistic study, FGF21 enhanced sirtuin 1 (SIRT1) binding to liver kinase B1 (LKB1) and then decreased LKB1 acetylation, subsequently inducing AMP-activated protein kinase (AMPK) activation, which improved the cardiac inflammation, oxidative stress, and apoptosis. These alterations were significantly prohibited by SIRT1 RNAi. The present work demonstrates for the first time that FGF21 obviously prevented DOX-induced cardiotoxicity via the suppression of oxidative stress, inflammation, and apoptosis through the SIRT1/LKB1/AMPK signaling pathway.
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影响因子：
4.8
作者：
Lan, Fan;Cacicedo, Jose M.;Ido, Yasuo
通讯作者：
Ido, Yasuo
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4.8
作者：
Feingold, Kenneth R.;Grunfeld, Carl;Kharitonenkov, Alexei
通讯作者：
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影响因子：
6.1
作者：
Sahu, Bidya Dhar;Kumar, Jerald Mahesh;Sistla, Ramakrishna
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Sistla, Ramakrishna