沙库巴曲缬沙坦钠通过Nrf2/HO-1信号通路缓解心力衰竭的机制研究  

Mechanistic study of Sacubitril/Valsartan in alleviating heart failure via the Nrf2/HO-1 signaling pathway

作　　者：刘圣山 裴兆辉 熊小英 宋国良 熊玲兵 刘衍冬 Liu Sheng-shan;Pei Zhao-hui;Xiong Xiao-ying;Song Guo-liang;Xiong Ling-bing;Liu Yan-dong(Department of Cardiology,The Third Hospital of Nanchang,Nanchang,Jiangxi 330009,China)

机构地区：[1]南昌市第三医院心血管内二科,江西南昌330009

出　　处：《中国现代医学杂志》2024年第19期35-43,共9页China Journal of Modern Medicine

基　　金：国家自然科学基金(No:82060351);江西省卫生健康委科技计划(No:202311276);南昌市科技支撑计划项目(No:2022-KJZC-013);南昌市医疗卫生引导性科技计划项目(No:2023YLWS035)。

摘　　要：目的 探究沙库巴曲缬沙坦钠通过Nrf2/HO-1信号通路改善心力衰竭(HF)细胞和动物模型的分子机制。方法 通过盐酸阿霉素(DOX)处理H9C2细胞后制备HF细胞模型,然后分别给予沙库巴曲缬沙坦钠(LCZ696)和Nrf2抑制剂(ML385)治疗。将实验细胞分为对照组、DOX组、DOX+LCZ696组、DOX+ML385组、DOX+LCZ696+ML385组。用DOX诱导HF模型小鼠,并给予LCZ696和ML385治疗,又分为假手术组、DOX组、DOX+LCZ696组、DOX+LCZ696+ML385组。CCK-8检测细胞活力;流式细胞术检测细胞凋亡;采用酶联免疫吸附试验(ELISA)检测细胞ROS、MDA、SOD水平,以及炎症因子(TNF-α、IL-1β、IL-6)蛋白浓度;Western blotting检测各组细胞和小鼠Bax、Bcl-2、C-Caspase-3、Nrf2和HO-1蛋白相对表达量。观察各组小鼠心脏组织HE、Masson和TUNEL染色。结果 与对照组比较,DOX组细胞活力降低(P <0.05),细胞凋亡率升高(P <0.05),炎症因子、ROS、MDA水平和促凋亡蛋白表达均升高(P <0.05),SOD水平、Nrf2和HO-1蛋白表达均降低(P <0.05);与DOX组比较,DOX+LCZ696组抑制了DOX造成的细胞损伤,而DOX+ML385组加重了细胞损伤程度;与DOX+LCZ696组比较,DOX+LCZ696+ML385组细胞损伤更为严重。而与DOX+ML385组比较,DOX+LCZ696+ML385组细胞损伤减轻。与假手术组比较,DOX诱导小鼠心脏组织损伤严重,DOX+LCZ696组则缓解了DOX造成的损伤,DOX+LCZ696+ML385组损伤加重。结论 沙库巴曲缬沙坦钠通过Nrf2/HO-1信号通路可缓解DOX诱导的心肌细胞损伤和小鼠心脏组织损伤。Objective To explore the molecular mechanism of Sacubitril/Valsartan Sodium improving heart failure cell model and animal model through Nrf2/HO-1 signaling pathway.Methods H9C2 cells were treated with Doxorubicin hydrochloride(DOX)to construct a heart failure cell model,and then treated with Sacubitril/Valsartan Sodium(LCZ696)and Nrf2 inhibitor(ML385),respectively.They were divided into five groups:Control,DOX,DOX+LCZ696,DOX+ML385,DOX+LCZ696+ML385.Mice model of heart failure was induced by DOX and treated with LCZ696 and ML385,which were divided into sham operation group,DOX group,DOX+LCZ696 group,and DOX+LCZ696+ML385 group.Cell viability and apoptosis was analyzed by CCK-8 and flow cytometry.ROS,MDA and SOD levels were detected with the kit.The levels of TNF-α,IL-1βand IL-6 were detected by ELISA.Bax,Bcl-2,C-caspase-3,Nrf2 and HO-1 proteins was detected via Western blotting.Heart tissue of mice with heart failure was stained by HE,Masson and TUNEL.Results Compared with control group,DOX-induced cell viability was significantly decreased(P<0.05);cell apoptosis ratio was increased(P<0.05);the levels of inflammatory factors,ROS,MDA,and pro-apoptotic proteins were increased(P<0.05);SOD level,Nrf2,and HO-1 proteins were decreased(P<0.05).Compared with DOX group,DOX+LCZ696 group significantly inhibited cell damage caused by DOX,while DOX+ML385 group significantly aggravated cell damage.Compared with DOX+LCZ696 group,the cell injury was more severe in DOX+LCZ696+ML385 group,while the cell injury was reduced in DOX+LCZ696+ML385 group.Compared with the sham group,the heart tissue damage of mice induced by DOX was serious,the damage caused by DOX was alleviated in DOX+LCZ696 group,and the damage was aggravated in DOX+LCZ696+ML385 group.Conclusion Sacubitril/Valsartan sodium alleviates DOX-induced myocardial cell injury through Nrf2/HO-1 signaling pathway.

关 键 词：心力衰竭 沙库巴曲缬沙坦钠 DOX Nrf2/HO-1通路 

分 类 号：R541.6[医药卫生—心血管疾病]