Cardamonin protects against doxorubicin-induced cardiotoxicity in mice by restraining oxidative stress and inflammation associated with Nrf2 signaling
Cardamonin protects against doxorubicin-induced cardiotoxicity in mice by restraining oxidative stress and inflammation associated with Nrf2 signaling
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DOI：
10.1016/j.biopha.2019.109547
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发表时间：
2020-02-01
影响因子：
7.5
通讯作者：
Wang Gang
中科院分区：
文献类型：
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作者：
Wang Qi;Wang Boliang;Wang Gang
阿霉素（DOX）的心脏毒性限制了其在肿瘤治疗中的临床应用。然而，DOX诱导的心肌病的基本病理生理分子机制尚未完全阐明，并且缺乏疾病特异性的治疗策略。本研究的目的是探讨豆蔻明（CAR），一种在高良姜植物中发现的黄酮，在小鼠模型中对DOX诱导的心脏毒性的潜在的心脏保护作用。首先，在DOX处理的小鼠心肌细胞中，CAR通过升高核因子红细胞-2相关因子2（Nrf 2）信号传导并减少Nrf 2的降解而显示出显著的细胞保护作用。该过程随后改善了抗氧化系统，如通过血红素加氧酶-1（HO 1）、NAD（P）H：醌氧化还原酶1（NQO 1）、谷氨酸-半胱氨酸连接酶修饰亚基（GCLM）、超氧化物歧化酶（SOD）、谷胱甘肽（GSH）和过氧化氢酶（CAT）的上调表达水平所证明的。相反，CAR处理高度抑制了DOX诱导的丙二醛（MDA）和活性氧（ROS）的增加。此外，CAR通过分别减少Caspase-3和核因子-κ B（NF-κ B）信号通路，减少心肌细胞中DOX诱导的细胞凋亡和炎症反应。然后，在DOX诱导的心脏毒性动物模型中，我们证实CAR通过改善Nrf 2信号通路，显著抑制小鼠心脏的氧化应激、凋亡和炎症反应，最终改善心脏功能。总之，我们的研究结果表明，CAR激活Nrf 2相关的细胞保护系统，并保护心脏免受氧化损伤，凋亡和炎症损伤，这表明CAR可能是预防DOX相关心肌病的潜在治疗策略。
The clinical application of doxorubicin (DOX) for cancer treatment is limited due to its cardiotoxicity. However, the basic pathophysiological molecular mechanisms underlying DOX-induced cardiomyopathy have not yet been completely clarified, and the disease-specific therapeutic strategies are lacking. The aim of the present study was to investigate the potential cardioprotective effect of cardamonin (CAR), a flavone found in Alpinia plant, on DOX-induced cardiotoxicity in a mouse model. At first, in DOX-treated mouse cardiomyocytes, CAR showed significantly cytoprotective effects through elevating nuclear factor erythroid-2 related factor 2 (Nrf2) signaling, and reducing the degradation of Nrf2. This process then improved the anti-oxidant system, as evidenced by the up-regulated expression levels of haem oxygenase-1 (HO1), NAD(P)H:quinone oxidoreductase 1 (NQO1), glutamate-cysteine ligase modifier subunit (GCLM), superoxide dismutase (SOD), glutathione (GSH) and catalase (CAT). In contrast, DOX-induced increases in malondialdehyde (MDA) and reactive oxygen species (ROS) were highly inhibited by CAR treatments. Additionally, DOX-induced apoptosis and inflammatory response in cardiomyocytes were diminished by CAR through reducing the Caspase-3 and nuclear factor-kappa B (NF-kappa B) signaling pathways, respectively. Then, in the DOX-induced animal model with cardiotoxicity, we confirmed that through improving Nrf2 signaling, CAR markedly suppressed oxidative stress, apoptosis and inflammatory response in hearts of mice, improving cardiac function eventually. Together, our findings demonstrated that CAR activated Nrf2-related cytoprotective system, and protected the heart from oxidative damage, apoptosis and inflammatory injury, suggesting that CAR might be a potential therapeutic strategy in the prevention of DOX-associated myocardiopathy.