文献类型：期刊文献

中文题名：当归黄芪超滤物通过调控ROS/GSH/GPx4轴抑制铁死亡改善放射性大鼠心肌纤维化

英文题名：Radix Angelica Sinensis and Radix Astragalus ultrafiltration extract improves myocardial fibrosis in radioactive rats by regulating ROS/GSH/GPx4 axis to inhibit ferroptosis

作者：任春贞[1,2,3];陈其林[1,2,4];张启立[4];吕欣芳[1,2,3];支晓东[1,2,3];高翔[1,2,3];吴雪[1,2];李晓静[1,2];刘凯[1,2,3];赵信科[1,2,3];李应东[1,2,3]

第一作者：任春贞

机构：[1]甘肃中医药大学中西医结合学院,甘肃兰州730000;[2]甘肃省中医药防治慢性病重点实验室,甘肃兰州730000;[3]甘肃中医药大学附属医院,甘肃兰州730000;[4]甘肃中医药大学药学院,甘肃兰州730000

第一机构：甘肃中医药大学中西医结合学院

年份：2024

卷号：40

期号：4

起止页码：723

中文期刊名：中国药理学通报

外文期刊名：Chinese Pharmacological Bulletin

收录：CSTPCD;;Scopus;北大核心:【北大核心2023】；CSCD:【CSCD2023_2024】；

基金：国家自然科学基金资助项目(No 82260869,82360926);甘肃教育揭榜挂帅项目(No 2021jyjbgs-03);甘肃省中医药防治重大疾病专项(No GZKZD-2018-02);甘肃省科技重大专项(No 20ZD7FA002);甘肃省陇原青年创新创业人才项目;甘肃省青年科技基金(No 23JRRA1217);2022年甘肃省优秀研究生“创新之星”基金(No 2022CXZX-736)。

语种：中文

中文关键词：当归黄芪超滤物;放射性心肌纤维化;铁死亡;氧化应激;ROS/GSH/GPx4轴;抗心肌纤维化

外文关键词：Radix Angelica Sinensis and Radix Astragalus ultrafiltration extract;radiation-induced myocardial fibrosis;ferroptosis;oxidative stress;ROS/GSH/GPx4 axis;anti-myocardial fibrosis

摘要：目的探讨ROS/GSH/GPx4轴介导的心肌铁死亡在放射性心肌纤维化中的作用机制及当归黄芪超滤物的干预作用。方法50只大鼠随机分为5组。除空白组外,其余各组大鼠均接受X射线单次局部胸部照射建立放射性心肌纤维化模型。辐射后,当归黄芪超滤物各组大鼠分别灌胃给药30 d后,用小动物超声评价心功能;比色法检测SOD、GSH、MDA及Fe^(2+)活性;免疫荧光检测ROS表达;HE、Masson染色观察病理变化及纤维化;透射电镜观察心肌超微结构;Western blot检测铁死亡及纤维化蛋白表达。结果与空白组比较,模型组LVEF和LVFS值降低;Fe^(2+)、MDA、ROS水平上升,SOD、GSH水平下降;HE及Masson显示有炎性细胞聚集及胶原纤维沉积;透射电镜显示受损线粒体数量增多、排列紊乱,形态不规则、变小、嵴紊乱;Western blot显示α-SMA、Collagen I、NOX1蛋白表达升高,GPx4、FTH1蛋白表达降低;与模型组比较,当归黄芪超滤物组大鼠心功能改善,ROS、抗氧化指标恢复,Fe^(2+)水平降低;线粒体结构及纤维化程度减轻;α-SMA、Collagen I、NOX1蛋白表达下降,GPx4、FTH1蛋白表达上升。结论当归黄芪超滤物对放射性心肌纤维化具有抑制作用,其机制可能是通过调控ROS/GSH/GPx4轴抑制心肌铁死亡发挥作用。
Aim To investigate the mechanism of ROS/GSH/GPx4 axis-mediated cardiomyocyte iron death in myocardial fibrosis in radioactive rats and the intervention of Radix Angelica Sinensis and Radix Astragalus ultrafiltration extract(RAS-RA).Methods Fifty Wistar rats were randomly divided into five groups of 10 rats in each.Except for the normal control group which was not irradiated,the rats in other groups were anaesthetised and received 40 Gy X-rays single local chest irradiation once to establish myocardial fibrosis in radioactive rats.After radiation,rats in each intervention group of RAS-RA were administered by gavage at doses of 0.12,0.24,and 0.48 g·kg^(-1),respectively,once/day for 30 consecutive days.After 30 consecutive days of administration,cardiac function of rats in each group was detected by small animal ultrasound;SOD,GSH,MDA and Fe^(2+)levels,indicators of oxidative stress,were detected by colorimetric method in cardiac tissue of each group;fluorescence intensity of reactive oxygen species(ROS)was detected by immunofluorescence in cardiac tissue;pathological morphology of cardiac tissue and fibrosis were observed by HE and Masson staining.And the rats in each group was used to observe the ultrastructural changes of myocardium by transmission electron microscopy.The protein expression levels of NOX1,GPx4,FTH1,CO1 andα-SMA in myocardial tissue were detected by Western blot.Results Compared with the blank group,the LVEF and FS values of rats in the model group were significantly reduced(P<0.05);Fe^(2+)level increased,MDA level increased,SOD and GSH level decreased(P<0.05);ROS level increased;HE and Masson showed that the cardiac cell morphology was irregularly arranged,with more inflammatory cell aggregation and collagen fibre deposition.Transmission electron microscopy showed that myofilament arrangement of cardiomyocytes in the model group was irregular and loosely arranged and disordered,myofilaments were broken and dissolved,the number of damaged mitochondria was significantly increased and disordered,mitochondrial morphology was irregular,mitochondrial cristae were disorganised,mitochondria became smaller,some mitochondria were swollen,outer membrane was ruptured,and mitochondria with iron death-specific characteristic alterations were present;Western blot showed that the expression ofα-SMA,collagen I,and NOX1 in cardiac tissue was significantly elevated(P<0.05),and GPX4 and FTH1 protein expression significantly decreased(P<0.05);compared with the model group,each intervention group of RAS-RA significantly improved the cardiac function of rats,with the recovery of lipid peroxidation and antioxidant-related indexes,and the reduction of Fe^(2+)level,the improvement of the structure and function of mitochondria,the reduction of the degree of fibrosis;and the myocardial tissue ofα-SMA,collagen I,NOX1 protein expression decreased(P<0.05),and GPX4,FTH1 protein expression injury increased(P<0.05).Conclusions RAS-RA inhibits myocardial fibrosis in radioactive rats,and the mechanism may be related to inhibiting myocardial iron death by regulating the ROS/GSH/GPx4 axis.