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首页> 外文期刊>Cellular Physiology and Biochemistry >Exogenous Hydrogen Sulfide Protects against Doxorubicin-Induced Inflammation and Cytotoxicity by Inhibiting p38MAPK/NFκB Pathway in H9c2 Cardiac Cells
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Exogenous Hydrogen Sulfide Protects against Doxorubicin-Induced Inflammation and Cytotoxicity by Inhibiting p38MAPK/NFκB Pathway in H9c2 Cardiac Cells

机译：外源性硫化氢通过抑制H9c2心脏细胞中的p38MAPK /NFκB途径来保护阿霉素诱导的炎症和细胞毒性

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Background/Aim:We have demonstrated that exogenous hydrogen sulfide (H2S) protects H9c2 cardiac cells against the doxorubicin (DOX)-induced injuries by inhibiting p38 mitogen-activated protein kinase (MAPK) pathway and that the p38 MAPKuclear factor-κB (NF-κB) pathway is involved in the DOX-induced inflammatory response and cytotoxicity. The present study attempts to test the hypothesis that exogenous H2S might protect cardiomyocytes against the DOX-induced inflammation and cytotoxicity through inhibiting p38 MAPK/NF-κB pathway. Methods: H9c2 cardiac cells were exposed to 5μM DOX for 24 h to establish a model of DOX cardiotoxicity. The cells were pretreated with NaHS( a donor of H2S) or other drugs before exposure to DOX. Cell viability was analyzed by cell counter kit 8 ( CCK-8), The expression of NF-κB p65 and inducible nitric oxide synthase (iNOS) was detected by Western blot assay. The levels of interleukin-1β (IL-1β), IL-6 and tumor necrosis factor-α (TNF-α) were tested by enzyme-linked immunosorbent assay (ELISA). Results: Our findings demonstrated that pretreatment of H9c2 cardiac cells with NaHS for 30 min before exposure to DOX markedly ameliorated the DOX-induced phosphorylation and nuclear translocation of NF-κB p65 subunit. Importantly, the pretreatment with NaHS significantly attenuated the p38 MAPK/NF-κB pathway-mediated inflammatory responses induced by DOX, as evidenced by decreases in the levels of IL-1β, IL-6 and TNF-α. In addition, application of NaHS or IL-1β receptor antagonist (IL-1Ra) or PDTC (an inhibitor of NF-κB) attenuated the DOX-induced expression of iNOS and production of nitric oxide (NO), respectively. Furthermore, IL-1Ra also dramatically reduced the DOX-induced cytotoxicity and phosphorylation of NF-κB p65. The pretreatment of H9c2 cells with N-acetyl-L-cysteine (NAC), a scavenger of reactive oxygen species (ROS) prior to exposure to DOX depressed the phosphorylation of NF-κB p65 induced by DOX. Conclusion: The present study has demonstrated the new mechanistic evidence that exogenous H2S attenuates the DOX-induced inflammation and cytotoxicity by inhibiting p38 MAPK/NF-κB pathway in H9c2 cardiac cells. We also provide novel data that the interaction between NF-κB pathway and IL-1β is important in the induction of DOX-induced inflammation and cytotoxicity in H9c2 cardiac cells.
机译：背景/目的：我们已经证明，外源性硫化氢（H 2 S）通过抑制p38丝裂原激活的蛋白激酶（MAPK）途径来保护H9c2心肌细胞免受阿霉素（DOX）诱导的伤害，并且p38 MAPK /核因子-κB（NF-κB）通路与DOX诱导的炎症反应和细胞毒性有关。本研究试图检验外源性H 2 S可能通过抑制p38 MAPK /NF-κB途径保护心肌细胞免受DOX诱导的炎症和细胞毒性的假说。方法：将H9c2心脏细胞暴露于5μMDOX中24小时，以建立DOX心脏毒性模型。在暴露于DOX之前，用NaHS（H 2 S的供体）或其他药物对细胞进行预处理。用细胞计数试剂盒8（CCK-8）分析细胞活力，用蛋白质印迹法检测NF-κBp65和诱导型一氧化氮合酶（iNOS）的表达。用酶联免疫吸附试验（ELISA）检测白细胞介素-1β（IL-1β），IL-6和肿瘤坏死因子-α（TNF-α）的水平。结果：我们的发现表明，在暴露于DOX之前，用NaHS预处理H9c2心肌细胞30分钟，可显着改善DOX诱导的NF-κBp65亚基的磷酸化和核易位。重要的是，用NaHS预处理可显着减弱DOX诱导的p38 MAPK /NF-κB途径介导的炎症反应，IL-1β，IL-6和TNF-α的水平降低证明了这一点。此外，使用NaHS或IL-1β受体拮抗剂（IL-1Ra）或PDTC（NF-κB抑制剂）分别减弱了DOX诱导的iNOS表达和一氧化氮（NO）的产生。此外，IL-1Ra还显着降低了DOX诱导的NF-κBp65的细胞毒性和磷酸化。在暴露于DOX之前，先用N-乙酰-L-半胱氨酸（NAC）预处理H9c2细胞，这是活性氧（ROS）的清除剂，可抑制DOX诱导的NF-κBp65的磷酸化。结论：本研究表明新的机制证据表明外源性H 2 S通过抑制H9c2心脏细胞中的p38 MAPK /NF-κB途径减轻DOX诱导的炎症和细胞毒性。我们还提供了新颖的数据，即NF-κB通路与IL-1β之间的相互作用在DOX诱导的H9c2心脏细胞炎症和细胞毒性的诱导中很重要。

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