Astragaloside IV Inhibits Doxorubicin-Induced Cardiomyocyte Apoptosis Mediated by Mitochondrial Apoptotic Pathway via Activating the PI3K/Akt Pathway

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概要

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• Doxorubicin (DOX) is a widely used antitumor drug whose application is seriously limited by its cardiotoxicity. Mitochondria-mediated cardiomyocyte apoptosis plays a critical role in DOX-induced cardiotoxicity (DIC). The aim of the present study was to investigate the protective effect of astragaloside IV (3-O-beta-<span style="font-variant: small-caps;">D</span>-xylopyranosyl-6-O-beta-<span style="font-variant: small-caps;">D</span>-glucopyranosyl-cycloastragenol, AS-IV), a pure saponin isolated from Astragalus membranaceus, against DOX-induced cardiomyocyte apoptosis in primary cultured neonatal rat cardiomyocytes. Immunocytochemistry and Microculture Tetrazolium (MTT) assays showed that AS-IV significantly reduced DOX-induced cardiomyocyte loss. Additionally, AS-IV markedly ameliorated DOX-caused cardiomyocyte dysfunction via restoring the beating cell ratio and beating rate in cardiomyocytes. Furthermore, AS-IV substantially reduced the mitochondrial reactive oxygen species (ROS) production and lactate dehydrogenase (LDH), creatine kinase-MB isoenzyme (CK-MB) and cytochrome c (CytC) release, and restored the reduced ATP level, succinate dehydrogenase (SDH) and ATP synthase activities induced by DOX, suggesting that AS-IV significantly attenuated DOX-induced mitochondrial damage and dysfunction. It was further observed that DOX-induced cardiomyocyte apoptosis, as qualitatively evaluated by Hoechst 33258 staining and accurately quantified by flow cytometry, was markedly inhibited by AS-IV. Western blot analysis manifested that AS-IV significantly inhibited the activation of mitochondrial apoptotic pathway (MAP) via inducing the phosphorylation of Akt and Bad. Furthermore, phosphatidylinositol 3-kinase (PI3K) inhibitor 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride (LY294002) remarkably inhibited the anti-apoptotic effect of AS-IV. Moreover, AS-IV didn't compromise the antitumor activity of DOX. Taken together, our findings indicate that AS-IV ameliorates DIC, and this beneficial effect appears to be dependent on the activation of the PI3K/Akt pathway. Thus, AS-IV may hold promise as an efficient cardioprotective agent against DIC.

著者

• Wu Yingliang

  Department Of Chemistry Nanchang University

• Cai Jiayi

  Department of Pharmacology, Shenyang Pharmaceutical University

• Pang Lili

  Department of Pharmacology, Shenyang Pharmaceutical University

• Zuo Daiying

  Department of Pharmacology, Shenyang Pharmaceutical University

• Wu Yingliang

  Department of Pharmacology, Shenyang Pharmaceutical University

• Jia Yuanyuan

  Department of Pharmacology, Shenyang Pharmaceutical University

• Li Zengqiang

  Department of Pharmacology, Shenyang Pharmaceutical University

• Liu Hanmo

  Department of Pharmacology, Shenyang Pharmaceutical University

• Dai Zhengning

  Department of Pharmacology, Shenyang Pharmaceutical University

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• Astragaloside IV Inhibits Doxorubicin-Induced Cardiomyocyte Apoptosis Mediated by Mitochondrial Apoptotic Pathway via Activating the PI3K/Akt Pathway

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