瑞舒伐他汀上调沉默信息调节因子2相关酶1/核转录因子-κB信号通路抑制阿霉素所致的心肌损伤的研究

摘要

Objective: To investigate the effects of rosuvastatin for up-regulating the expression of Sirt1/NF-κB signal pathway and inhibiting doxorubicin (DOX)-induced cardiotoxicity injury in experimental mice. Methods: A total of 30 male C57 BL/6J mice at (4-6) weeks of age were randomly divided into 3 groups. Treatment group, the mice received intra-gastric rosuvastatin for 7 days, followed by intra-peritoneal injection of DOX 15mg/kg to induce the cardiotoxicity injury, and then received rosuvastatin for another 5 days. Model group, the mice received intra-peritoneal injection of DOX 15mg/kg to induce the cardiotoxicity injury, and then received intra-gastric normal saline for the same volume. Control group, the mice received intra-gastric normal saline for the same volume. n=10 in each group. The mice were killed at 12 days after treatment. The pathological change in myocardial tissue was observed by HE staining, the myocardial oxidative stress indexes of malonadehyde (MDA) level and super oxide dismutase (SOD) activity were measure by the operating kits and the protein expression of Sirt1/NF-κB was examined by immunohistochemistry. Results: Compared with Control group, Model group had obviously increased levels of MDA, NF-κB and decreased SOD activity, Sirt1 level, all P<0.05;the mice in Model group showed disordered myocardial structure with inlfammatory cell inifltration. Compared with Model group, Treatment group had obviously decreased levels of MDA, NF-κB (while they were still higher than Control group), and increased SOD activity, Sirt1 level, all P<0.05;the mice in Treatment group showed intact myocardial structure with much less edema and lymphocyte inifltration. Conclusion: Sirt1/NF-κB signal pathway was involved in DOX-induced cardiotoxicity injury in experimental mice, rosuvastatin could protect the injury via up-regulating the expression of Sirt1/NF-κB signal pathway.%目的：探讨沉默信息调节因子2相关酶1/核转录因子-κB（Sirt1/NF-κB）信号通路在抗肿瘤药阿霉素诱导的心肌损伤中的作用及瑞舒伐他汀钙的干预效果。　　方法：将30只4~6周龄雄性C57BL/6J小鼠随机分为对照组、模型组和干预组，每组各10只。干预组预先给予瑞舒伐他汀钙稀释灌胃7天后，干预组和模型组分别给予阿霉素15 mg/kg腹腔注射建立心肌损伤模型，建模后干预组继续瑞舒伐他汀干预5天，同时模型组与对照组给予等量生理盐水灌胃。12天后，处死全部小鼠取心脏组织，多聚甲醛固定，经石蜡包埋、切片、苏木精-伊红（HE）染色后，观察各组小鼠心肌病理变化；取心肌组织匀浆检测氧化应激指标丙二醛（MDA）含量、超氧化物歧化酶（SOD）活力；免疫组化法测各组小鼠心肌Sirt1/NF-κB表达水平。　　结果：与对照组相比，模型组心肌匀浆MDA含量、心肌组织NF-κB水平均明显升高，匀浆SOD活力、心肌组织Sirt1水平均显著降低（P<0.05），差异均有统计学意义，且心肌结构紊乱、炎症细胞浸润明显；与模型组比较，干预组MDA含量、NF-κB水平均明显下降但仍高于对照组，匀浆SOD活力、心肌Sirt1水平均升高（P<0.05），差异有统计学意义，且心肌结构完整、细胞水肿及淋巴浸润明显减少。　　结论：Sirt1/NF-κB信号通路参与了阿霉素诱导的心肌损伤过程，瑞舒伐他汀能通过上调该信号通路保护阿霉素所致的心肌毒性损伤。