摘要
目的探讨肺心汤对低氧性肺动脉高压(HPH)大鼠的保护作用及潜在机制。方法将48只雄性SD大鼠随机分为对照组、模型组、肺心汤低、中、高剂量组(5.85、11.7、23.4 g·kg^(-1))及西地那非阳性对照组(25mg·kg^(-1)),每组8只,每日灌胃给药后置入低氧舱8h,连续3周;右心导管法测定各组大鼠右心室收缩压(RVSP),小动物心脏超声系统测定三尖瓣环收缩期位移(TAPSE)、右心室壁厚度(RVAWT)、右心室肥厚指数(RVHI)、肺动脉血流加速时间(PAAT)及肺动脉射血时间(PET);苏木精-伊红(HE)染色评估大鼠肺动脉重构情况;透射电镜观察肺动脉线粒体亚显微结构;腺嘌呤核苷三磷酸(ATP)试剂盒检测肺组织ATP水平;活性氧(ROS)测试剂盒检测肺组织ROS水平;RT-PCR检测大鼠肺组织抵抗素样分子β(RELM-β)、动力相关蛋白1(DRP1)及线粒体分裂蛋白1(FIS1)mRNA水平;免疫组化测定大鼠肺动脉RELM-β表达水平;免疫荧光检测大鼠肺动脉DRP1、FIS1表达水平。结果与对照组比较,模型组RVSP、RVAWT明显升高,TAPSE、PAAT明显降低,肺血管出现明显重塑,线粒体超微结构损伤明显(P<0.01),ROS水平上升(P<0.01),ATP生成减少(P<0.01),RELM-β、DRP1和FIS1 mRNA及蛋白水平明显上升(P<0.01);与模型组比较,肺心汤中、高剂量组RVSP、RVAWT明显降低,TAPSE、PAAT明显升高,肺动脉重塑及线粒体损伤明显改善(P<0.01),ROS水平减少(P<0.01),ATP生成增加(P<0.01),RELM-β、DRP1和FIS1 mRNA及蛋白水平明显下调(P<0.01)。结论肺心汤可能通过抑制RELM-β/DRP1通路改善线粒体损伤分裂,减少ROS水平,回调ATP生成,缓解HPH大鼠的肺血管重构及右心功能。
Objective Investigating the protective effects and potential mechanisms of Feixin Decoction in rats with hypoxic pulmonary hypertension(HPH).Methods Forty-eight male SD rats were randomly allocated into the control,model,Feixin Decoction groups(12.75 mg·kg^(-1)、25.5 mg·kg^(-1)、51 mg·kg^(-1))as well as the sildenafil positive control group(25mg·kg^(-1)),each group consisting of 8 rats.They were exposed to a hypoxic chamber for 8 hours daily after oral administration for 3 weeks.The right ventricular systolic pressure(RVSP)was assessed via right heart catheterization in all groups.Tricuspid annular systolic displacement(TAPSE),right ventricular anterior wall thickness(RVAWT),right ventricular hypertrophy index(RVHI),pulmonary arterial acceleration time(PAAT),and pulmonary arterial ejection time(PET)were evaluated using a small-animal cardiac ultrasound system.Hematoxylin-eosin(HE)staining was used to evaluate the remodeling of rat pulmonary arteries,while transmission electron microscopy was employed to observe the submicroscopic structure of mitochondria in rat pulmonary arteries.Adenosine triphosphate(ATP)kit is available to detect ATP level in rat lung tissue;reactive oxygen species(ROS)kit is used to detect ROS level in lung tissue;RT-PCR was used to detect the mRNA levels of resistin oxygen moleculeβ(RELM-β),dynamin-related protein 1(DRP1),and mitochondrial fission protein 1(FIS1)in rat lung tissues;immunohistochemistry was performed to determine the expression levels of RELM-βin rat pulmonary arteries;and immunofluorescence was used to measure the expression levels of DRP1 and FIS1 in rat pulmonary arteries.Results The model group exhibited a notable rise in RVSP and RVAWT,along with a decrease in TAPSE and PAAT compared to the control group.Significant alterations were observed in the pulmonary vasculature,mitochondrial microstructure damage(P<0.01),elevated ROS levels(P<0.01),reduced ATP production(P<0.01),and notably increased levels of RELM-β,DRP1,and FIS1 mRNA and proteins(P<0.01).Compared to the model group,RVSP and RVAWT were significantly reduced,TAPSE and PAAT were significantly increased in the medium and high dose groups of Feixin Decoction(P<0.01).Additionally,pulmonary vascular remodeling and mitochondrial damage showed significant improvement(P<0.01),ROS level were reduced(P<0.01),ATP production increased(P<0.01),and there was a significant down-regulation of RELM-β,DRP1,and FIS1 mRNA and protein levels(P<0.01)in the medium and high dose groups of Feixin Decoction.Conclusion Feixin Decoction may improve mitochondrial damage,decrease ROS levels,regulate ATP production,and ease pulmonary vascular remodeling and right heart function in HPH rats by blocking the RELM-β/DRP1 pathway.
作者
丁蓉珍
谢海平
张超
易健
彭果然
程贝贝
曹闲雅
谭骏岚
戴爱国
DING Rong-zhen;XIE Hai-ping;SUN Yin-hui;ZHANG Chao;YI Jian;LI Xia;WANG Fei-ying;PENG Guo-ran;CHENG Bei-Bei;CAO Xian-ya;TAN Jun-lan;TAN Zhen-fei;SU Xian-li;DAI Ai-guo(Department of Respiralory Diseases,Medical School,Hunan University of Chinese Medicine,Changsha 410208,Hunan,China;Hunan Provincial Key Laboratory of Vascular Biology and Translational Medicine,Changsha 410208,Hunan,China;Department of Respiratory Medicine,First Affiliated Hospital,Hunan University of ChineseMedicine,Changsha 410021,Hunan,China;Department of Urinary Surgery,First Affiliated Hospital,Hunan University of Chinese Medicine,Changsha 410021,China)
出处
《时珍国医国药》
CSCD
北大核心
2024年第15期3348-3355,共8页
Lishizhen Medicine and Materia Medica Research
基金
湖南省自然科学基金青年项目(2024JJ6339)
湖南省教育厅优秀青年项目(22B0383)
长沙市自然基金项目(kq2208184)
湖南省中药粉体与创新药物研究省部共建国家重点实验室培育基地开放基金(2022FTKFJJ01)
中西医结合学院-明康中锦联合基金项目(2022MKZJ04)。
