Hydrogen sulfide protects H9c2 cardiac cells against doxorubicin-induced cytotoxicity through the PI3K/Akt/FoxO3a pathway
Hydrogen sulfide protects H9c2 cardiac cells against doxorubicin-induced cytotoxicity through the PI3K/Akt/FoxO3a pathway
复制标题
硫化氢通过 PI3K/Akt/FoxO3a 途径保护 H9c2 心肌细胞免受阿霉素诱导的细胞毒性
DOI：
10.3892/ijmm.2016.2563
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发表时间：
2016-06-01
影响因子：
5.4
通讯作者：
Jiang, Zhi-Sheng
中科院分区：
文献类型：
--
作者：
Liu, Mi-Hua;Zhang, Yuan;Jiang, Zhi-Sheng
多柔比星（DOX）是一种用于癌症治疗的有效药物，它也会产生活性氧（ROS），诱导严重的细胞毒性，这限制了它的临床应用。硫化氢（H2S）是一种新型的气体递质，已被证明具有保护心脏的作用。本研究旨在确定外源性H2S是否保护H9c2心肌细胞免受dox诱导的细胞毒性，以及这些保护作用是否通过PI3K/Akt/FoxO3a途径介导。将H9c2心肌细胞暴露于5 μ M DOX中24 h，建立DOX诱导的心脏毒性模型。结果表明，在DOX暴露前用氢硫化钠（NaHS）处理H9c2心肌细胞30 min，可显著减弱Akt和FoxO3a的磷酸化。值得注意的是，NaHS预处理H9c2细胞后，FoxO3a的核定位明显减弱，DOX诱导的H9c2细胞凋亡也明显减弱。在暴露于DOX之前，用n -乙酰- l-半胱氨酸（n -acetyl- l-半胱氨酸，一种ROS清除剂）处理H9c2细胞，也显著增加了Akt和FoxO3a的磷酸化，而这种磷酸化被DOX单独抑制。此外，PI3K/Akt选择性抑制剂LY294002预处理可逆转H2S对dox诱导心肌细胞损伤的保护作用，凋亡细胞数量增加，细胞活力降低，Akt和FoxO3a磷酸化水平降低。这些发现表明，外源性H2S通过PI3K/Akt/FoxO3a途径减弱dox诱导的H9c2心肌细胞的细胞毒性作用。
Doxorubicin (DOX) is an efficient drug used in cancer therapy that also produces reactive oxygen species (ROS) that induces severe cytotoxicity, which limits its clinical application. Hydrogen sulfide (H2S), a novel gasotransmitter, has been shown to exert cardioprotective effects. The present study aimed to determine whether exogenous H2S protects H9c2 cardiac cells against DOX-induced cytotoxicity and whether these protective effects are mediated through the PI3K/Akt/FoxO3a pathway. The H9c2 cardiac cells were exposed to 5 mu M DOX for 24 h to establish a model of DOX-induced cardiotoxicity. The results showed that the treatment of H9c2 cardiac cells with sodium hydrosulfide (NaHS) for 30 min prior to DOX exposure markedly attenuated the phosphorylation of Akt and FoxO3a. Notably, pre-treatment of the H9c2 cells with NaHS significantly attenuated the nuclear localization of FoxO3a as well as the apoptosis of H9c2 cells induced by DOX. The treatment of H9c2 cells with N-acetyl-L-cysteine (NAC), a scavenger of ROS, prior to DOX exposure, also markedly increased the phosphorylation of Akt and FoxO3a which was inhibited by DOX alone. Furthermore, pre-treatment with LY294002, a selective inhibitor of PI3K/Akt, reversed the protective effect of H2S against DOX-induced injury of cardiomyocytes, as demonstrated by an increased number of apoptotic cells, a decrease in cell viability and the reduced phosphorylation of Akt and FoxO3a. These findings suggested that exogenous H2S attenuates DOX-induced cytotoxic effects in H9c2 cardiac cells through the PI3K/Akt/FoxO3a pathway.