臭灵丹草调控Nrf2/SLC7A11/GPX4信号通路抑制铁死亡改善慢性心力衰竭的机制研究  

The mechanism of Laggerae Herba in improving chronic heart failure by inhibiting ferroptosis through the Nrf2/SLC7A11/GPX4 signaling pathway

作　　者：肖金陵 黄凯 魏小棋 范昕怡 柴王静 韩静 高阔 于雪 李芳赫 郭淑贞 XIAO Jinling;HUANG Kai;WEI Xiaoqi;FAN Xinyi;CHAI Wangjing;HAN Jing;GAO Kuo;YU Xue;LI Fanghe;GUO Shuzhen(School of Traditional Chinese Medicine,Beijing University of Chinese Medicine,Beijing 102488,China;Institute of Traditional Chinese Medicine,Beijing University of Chinese Medicine,Beijing 102488,China)

机构地区：[1]北京中医药大学中医学院,北京102488 [2]北京中医药大学中医药研究院

出　　处：《北京中医药大学学报》2025年第3期343-353,共11页Journal of Beijing University of Traditional Chinese Medicine

基　　金：国家自然科学基金项目(No.81922075,No.82174206)。

摘　　要：目的探讨清热解毒药臭灵丹草调控核转录因子红系2相关因子2(Nrf2)/溶质载体家族7成员11(SLC7A11)/谷胱甘肽过氧化物酶4(GPX4)信号通路抑制铁死亡,改善横主动脉弓缩窄诱导的慢性心力衰竭小鼠的作用及其机制。方法将24只雄性ICR小鼠按随机数字表法分为假手术组(n=6)和横主动脉弓缩窄组(n=18),横主动脉弓缩窄组行横主动脉缩窄术制备慢性心力衰竭模型。横主动脉弓缩窄组造模后按随机数字表法分为模型组、卡托普利组、臭灵丹草组,每组6只。卡托普利组(15 mg/kg)、臭灵丹草组(1.95 g/kg)灌胃相应药物,假手术组和模型组均灌胃等体积超纯水,每日1次,连续4周。治疗后,超声检测各组小鼠心脏功能相关指标;测量心脏质量及胫骨长度,计算心脏质量与胫骨长度比;苏木精-伊红染色观察小鼠心肌组织病理变化;Masson染色观察小鼠心肌组织纤维化程度;小麦胚芽凝集素(WGA)染色观察小鼠心肌细胞肥大程度;普鲁士蓝染色观察小鼠心肌组织铁沉积;酶联免疫吸附测定法检测小鼠血清氨基末端脑利钠肽前体(NT-proBNP)、谷胱甘肽(GSH)含量;比色法检测小鼠血清丙二醛(MDA)含量;蛋白质印迹法检测小鼠心脏组织Nrf2、GPX4、SLC7A11和铁蛋白重链1(FTH1)蛋白表达。结果与假手术组比较,模型组小鼠射血分数(EF)、短轴缩短率(FS)降低,左室收缩末期容积(LVESV)、左室收缩末期内径(LVESD)升高,左室前壁收缩末期厚度(LVAWs)、左室后壁收缩末期厚度(LVPWs)降低,心脏质量与胫骨长度比升高,心肌组织形态改变,心肌纤维化增加,心肌细胞横截面积增大,心肌组织出现铁沉积,血清NT-proBNP、MDA升高,GSH降低,心脏组织Nrf2、GPX4、SLC7A11、FTH1蛋白表达降低(P<0.05)。与模型组比较,卡托普利组和臭灵丹草组小鼠EF、FS、LVAWs升高,LVESV、LVESD降低,心脏质量与胫骨长度比降低,心肌细胞排列整齐,心肌纤维化程度降低,心肌细胞Objective To investigate the role and mechanism of the heat-clearing and detoxifying drug Laggerae Herba in regulating the nuclear factor-erythroid 2-related factor-2(Nrf2)/solute carrier family 7 member 11(SLC7A11)/glutathione peroxidase 4(GPX4)signaling pathway to inhibit ferroptosis and improve chronic heart failure induced by transverse aortic arch constriction in mice.Methods Twentyfour male ICR mice were divided into the sham(n=6)and transverse aortic arch constriction groups(n=18)according to the random number table method.The transverse aortic arch constriction group underwent transverse aortic constriction surgery to establish models.After modeling,the transverse aortic arch constriction group was further divided into the model,captopril,and Laggerae Herba groups according to the random number table method,with six mice per group.The captopril(15 mg/kg)and Laggerae Herba groups(1.95 g/kg)received the corresponding drugs by gavage,whereas the sham operation and model groups were administered the same volume of ultrapure water by gavage once a day for four consecutive weeks.After treatment,the cardiac function indexes of mice in each group were detected using ultrasound.The heart mass and tibia length were measured to calculate the ratio of heart weight to tibia length.Hematoxylin and eosin staining were used to observe the pathological changes in myocardial tissue.Masson staining was used to observe the degree of myocardial fibrosis.Wheat germ agglutinin staining was used to observe the degree of myocardial cell hypertrophy.Prussian blue staining was used to observe the iron deposition in myocardial tissue.An enzyme-linked immunosorbent assay was used to detect the amino-terminal pro-brain natriuretic peptide(NT-proBNP)and glutathione(GSH)contents in mice serum.Colorimetry was used to detect the malondialdehyde(MDA)content in mice serum.Western blotting was used to detect the Nrf2,GPX4,SLC7A11,and ferritin heavy chain 1(FTH1)protein expressions in mice cardiac tissue.Results Compared with the sham group,i

关 键 词：慢性心力衰竭 臭灵丹草 压力超负荷 铁死亡 小鼠 

分 类 号：R285.5[医药卫生—中药学]