Higenamine Combined with [6]-Gingerol Suppresses Doxorubicin-Triggered Oxidative Stress and Apoptosis in Cardiomyocytes via Upregulation of PI3K/Akt Pathway.
Higenamine Combined with [6]-Gingerol Suppresses Doxorubicin-Triggered Oxidative Stress and Apoptosis in Cardiomyocytes via Upregulation of PI3K/Akt Pathway.
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去甲乌药碱联合 [6]-姜酚通过上调 PI3K/Akt 通路抑制阿霉素引发的氧化应激和心肌细胞凋亡
DOI：
10.1155/2013/970490
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发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Liao XX
中科院分区：
文献类型：
--
作者：
Chen YL;Zhuang XD;Xu ZW;Lu LH;Guo HL;Wu WK;Liao XX
四逆汤是一个著名的中药方剂，多年来一直被用于治疗心血管疾病。先前，我们证明了四逆汤预防体内阿霉素诱导的心力衰竭。然而，其活性成分仍不清楚。因此，我们研究了四逆汤的活性成分及其在体外乳鼠心肌细胞和H9 c2细胞系阿霉素诱导的细胞毒性模型中的心脏保护机制。我们的研究结果表明，去甲乌药碱或[6]-姜辣素治疗增加多柔比星损伤的心肌细胞的活力。此外，去甲乌药碱和[6]-姜辣素的联合使用比任何一种药物作为单一药物产生更深刻的保护作用，其作用与临床批准的心脏保护剂右雷佐生相似。此外，我们发现阿霉素处理降低了SOD活性，增加了ROS的产生，增加了MDA的形成，诱导了LDH的释放，并触发了心肌细胞内在的MDA依赖性凋亡途径，而去甲乌药碱和[6]-姜辣素的共同处理则抑制了这一途径。最重要的是，去甲乌药碱加[6]-姜辣素的细胞保护作用可以被PI 3 K抑制剂LY 294002所消除。总之，去甲乌药碱和[6]-姜辣素的组合通过激活PI 3 K/Akt信号通路而对阿霉素诱导的心脏毒性发挥心脏保护作用。去甲乌药碱和[6]-姜辣素可能是四逆汤的有效成分。
Sini decoction is a well-known formula of traditional Chinese medicine, which has been used to treat cardiovascular disease for many years. Previously, we demonstrated that Sini decoction prevented doxorubicin-induced heart failure in vivo. However, its active components are still unclear. Thus, we investigated the active components of Sini decoction and their cardioprotective mechanisms in the in vitro neonatal rat cardiomyocytes and H9c2 cell line models of doxorubicin-induced cytotoxicity. Our results demonstrated that treatment with higenamine or [6]-gingerol increased viability of doxorubicine-injured cardiomyocytes. Moreover, combined use of higenamine and [6]-gingerol exerted more profound protective effects than either drug as a single agent, with effects similar to those of dexrazoxane, a clinically approved cardiac protective agent. In addition, we found that treatment with doxorubicin reduced SOD activity, increased ROS generation, enhanced MDA formation, induced release of LDH, and triggered the intrinsic mitochondria-dependent apoptotic pathway in cardiomyocytes, which was inhibited by cotreatment of higenamine and [6]-gingerol. Most importantly, the cytoprotection of higenamine plus [6]-gingerol could be abrogated by LY294002, a PI3K inhibitor. In conclusion, combination of higenamine and [6]-gingerol exerts cardioprotective effect against doxorubicin-induced cardiotoxicity through activating the PI3K/Akt signaling pathway. Higenamine and [6]-gingerol may be the active components of Sini decoction.