姜黄素通过心肌血红素加氧酶1基因干预铁死亡和自噬抗心力衰竭的机制  

Mechanism of curcumin intervening in iron death and autophagy against heart failure through HMOX-1 gene

作　　者：袁雪 刘占豪 钟昊 张芳芳 侯晓华 YUAN Xue;LIU Zhanhao;ZHONG Hao;ZHANG Fangfang;HOU Xiaohua(Department of Thoracic Surgery,Cangzhou People’s Hospital,Medical College,Cangzhou 061000,China;Department of Cardiac Surgery,Cangzhou People’s Hospital,Cangzhou 061000,China;Department of Orthopaedics,Renqiu Hospital of Traditional Chinese Medicine,Renqiu 062550,China;Department of Infection Control,Raoyang County People’s Hospital,Hengshui 053900,China)

机构地区：[1]沧州市人民医院医专胸外科,沧州061000 [2]沧州市人民医院心外科,沧州061000 [3]任丘市中医院骨外科,任丘062550 [4]河北省饶阳县人民医院感控科,衡水053900

出　　处：《西北药学杂志》2024年第6期38-45,共8页Northwest Pharmaceutical Journal

基　　金：河北省2022年度医学科学研究课题计划项目(编号:20220304)。

摘　　要：目的基于心肌血红素加氧酶1(heme oxygenase−1,HMOX−1)基因探讨姜黄素(curcumin,Cur)对心力衰竭(heart failure,HF)大鼠心肌的保护作用。方法纳入48只SD大鼠,随机选取8只大鼠作为对照组,其余大鼠进行腹主动脉缩窄手术。建模成功后,将大鼠随机分为HF组、Cur组、载体病毒(sh-NC)组、Hmox1基因敲减病毒(sh-Hmox1)组及Cur+sh-Hmox1组,每组8只。sh-NC组、sh-Hmox1组分别心肌定点注射sh-NC、sh-Hmox1-腺相关病毒(adeno-associated virus,AAV),4周后与对照组、HF组共同灌胃蒸馏水,Cur组予以400 mg·kg^(−1)灌胃,均每日1次,连续灌胃8周。用超声心动图和苏木精-伊红染色法(hematoxylineosin,HE)分别评估心功能及心肌组织病理形态;比色法检测血清铁水平;酶联免疫吸附试验(enzyme-linked immuno sorbent assay,ELISA)测定血清脑钠肽(brain natriuretic peptide,BNP)、铁蛋白水平、心肌组织活性氧(reactive oxygen species,ROS)水平和超氧化物歧化酶(superoxide dismutase,SOD)活性;用透射电子显微镜(transmission electron microscope,TEM)观察自噬体、线粒体的微观结构;Western blotting检测铁死亡相关标志物[溶质载体家族7成员11(solute carrier family 7 member 11,SLC7A11)、谷胱甘肽过氧化酶4(glutathione peroxidase 4,GPX4)]和自噬相关标志物(LC3Ⅱ、Beclin1、p62)蛋白的表达。结果与对照组比较,HF组大鼠的血清铁、铁蛋白、BNP水平、心肌组织中的SOD活性和SLC7A11、GPX4、LC3Ⅱ、Beclin1蛋白表达均显著降低,ROS水平和p62蛋白表达均显著升高(P<0.01);心肌细胞肥大伴炎性细胞浸润;TEM显示线粒体肿胀减轻、自噬小体增加;在HF组中,Cur给药逆转了上述指标的变化趋势(P<0.05);sh-Hmox1注射后,抑制了Cur对HF组上述指标的改善作用(P<0.05)。结论Cur可通过上调HMOX−1基因表达抑制铁死亡指标的表达水平,促进自噬,减轻心肌氧化应激,缓解HF大鼠的心肌损伤。Objective This study examines the protective effects of curcumin(Cur)on the myocardium of rats with heart failure,focusing on the heme oxygenase−1(HMOX−1)gene.Methods In this study,a total of 48 Sprague-Dawley(SD)rats were utilized.Initially,8 rats were randomly selected to serve as the control group,while the remaining rats underwent abdominal aortic coarctation to establish a model for the experiment.Following successful modeling,the rats were randomly assigned to 5 groups:The heart failure(HF)group,the Cur group,the vector virus(sh-NC)group,the Hmox1 gene knockdown virus(sh-Hmox1)group,and the Cur+sh-Hmox1 group,with each group comprising 8 rats.The sh-NC and sh-Hmox1 groups received injections of sh-NC and sh-HMOX1-adeno-associated virus(AAV),respectively.After a period of 4 weeks,rats in the sh-NC and sh-Hmox1 groups were administered distilled water via gavage once daily,while those in the Cur group received curcumin at a dosage of 400 mg·kg^(−1) by gavage once daily.This intragastric administration continued for 8 weeks.To assess cardiac function and the pathological morphology of myocardial tissue,echocardiography and hematoxylin-eosin(HE)staining were employed.Serum iron levels were determined using colorimetry.Additionally,enzyme-linked immunosorbent assay(ELISA)was utilized to measure serum brain natriuretic peptide(BNP),ferritin levels,reactive oxygen species(ROS)levels,and superoxide dismutase(SOD)activity in myocardial tissue.Transmission electron microscopy(TEM)was employed to observe the microstructure of autophagosomes and mitochondria.Furthermore,Western blotting analysis was conducted to examine the expression of 7 iron death-related markers,including solute carrier family members 11 and 7(SLC7A11),glutathione peroxidase 4(GPX4),as well as autophagy-related markers such as LC3Ⅱ,Beclin1,and p62 protein expression.Results In comparison to the control group,the HF group exhibited significant reductions in serum iron,ferritin,and BNP levels,as well as decreased SOD activity and diminished

关 键 词：心力衰竭 姜黄素 血红素加氧酶1基因 铁死亡 自噬 

分 类 号：R966[医药卫生—药理学]