槲皮素可改善大鼠肺动脉高压:基于调控HMGB1/RAGE/NF-κB通路  

Quercetin improves pulmonary arterial hypertension in rats by regulating the HMGB1/RAGE/NF-κB pathway

作　　者：张宁宁 邱奇 陈永锋[1,2] 孙正宇 卢国庆 王磊 康品方[1,2] 王洪巨[1] ZHANG Ningning;QIU Qi;CHEN Yongfeng;SUN Zhengyu;LU Guoqing;WANG Lei;KANG Pingfang;WANG Hongju(The Department of Cardiovascular Medicine,the First Affiliated Hospital of Bengbu Medical College,Teaching and Research Section of Physiology,Benbu Medical College,Bengbu 233000,China;Research Center for Cardiovascular and Cerebrovascular Diseases,Teaching and Research Section of Physiology,Benbu Medical College,Bengbu 233000,China)

机构地区：[1]蚌埠医学院第一附属医院心血管内科,安徽蚌埠233000 [2]蚌埠医学院心脑血管病研究中心,生理学教研室,安徽蚌埠233000

出　　处：《南方医科大学学报》2023年第9期1606-1612,共7页Journal of Southern Medical University

基　　金：国家自然科学基金(81970313);安徽省高校协同创新项目(GXXT-2020-019)安徽省自然科学基金(1908085QH353);安徽省自然科学基金(2208085MH192);安徽省高校科学研究项目(YJS20210541);蚌埠医学院研究生创新计划(Byycx22029)。

摘　　要：目的研究槲皮素是否通过HMGB1/RAGE/NF-κB改善肺动脉高压(PAH)。方法构建缺氧性肺动脉高压大鼠模型,分别设置对照组(CON组)、缺氧组(Hypoxia组)、缺氧+槲皮素组(Hypoxia+Que),治疗组每日以槲皮素100 mg/kg灌胃处理。以生物信号采集系统监测并测定右心室压力(RVSP)作为肺动脉收缩压,右心室肥厚指数(RVHI)评估右室肥厚程度。HE染色观察肺小动脉重构情况。通过小动物超声仪评估各组大鼠右心功能,通过蛋白质免疫印迹检测各组大鼠肺组织的HMGB1、RAGE、NF-κB,凋亡标志物Bax、Bcl-2和Cleved-caspase3的蛋白水平。结果与CON组相比,Hypoxia组RVHI增加和RVSP升高(P<0.01),槲皮素干预后降低RVHI和RVSP(P<0.01)。HE染色观察到Hypoxia组肺动脉血管壁明显增殖增厚和管腔狭窄,Hypoxia+Que组管壁增厚减轻和管径增大。小动物超声显示Hypoxia组RVFW增加和PAT/PET比值降低(P<0.01),Hypoxia+Que组较Hypoxia组RVFW降低和PAT/PET比值升高(P<0.01)。Western blot结果显示,与CON组相比,Hypoxia组HMGB1蛋白表达升高(P<0.01),RAGE、NF-κB、Bcl-2蛋白表达升高(P<0.01),Bax、Cleved-caspase3蛋白表达减少(P<0.01),Hypoxia+Que组HMGB1蛋白和NF-κB蛋白表达降低(P<0.05),RAGE蛋白表达降低(P<0.01)、Bcl-2蛋白表达降低(P<0.05),Bax蛋白和Cleved-caspase3蛋白表达升高(P<0.01)。结论槲皮素可能通过HMGB1/RAGE/NF-κB通路促进凋亡改善肺动脉高压。Objective To explore the mechanism through which quercetin improves pulmonary arterial hypertension(PAH).Methods Rat models of hypoxic pulmonary hypertension were established by exposure to hypoxia for 8-10 h each day(6 days a week for 4 weeks),and before each hypoxic exposure,the rats were given intragastric administration of 100 mg/kg quercetin or saline.After the treatments,the right ventricular systolic pressure(RVSP)and pulmonary artery systolic pressure of the rats were recorded.The right ventricular hypertrophy index(RVHI)was measured to evaluate right ventricular hypertrophy.HE staining was used to observe the remodeling of the pulmonary arterioles.The right cardiac function of the rats was evaluated by ultrasound.The protein levels of HMGB1,RAGE,NF-κB,Bax,Bcl-2 and cleaved caspase-3 in the lung tissue of the rats were detected using Western blotting.Results Compared with the rats maintained in normoxia,the rats with chronic hypoxic exposure showed significantly increased RVHI and RVSP(P<0.01),which were obviously lowered by quercetin treatment(P<0.01).HE staining showed significant pulmonary artery wall thickening with reduced lumen diameter in hypoxia group,and quercetin treatment effectively improved pulmonary vascular remodeling.Ultrasound examination revealed a significantly increased RVFW and a lowered PAT/PET ratio in hypoxia group(P<0.01),and such changes were ameliorated by quercetin treatment(P<0.01).Chronic hypoxia significantly increased the protein expressions of HMGB1(P<0.01),RAGE,NF-κB and Bcl-2(P<0.01)and lowered the protein expressions of Bax and cleaved caspase-3(P<0.01);Quercetin treatment obviously lowered the protein expressions of HMGB1,NF-κB(P<0.05),RAGE(P<0.01)and(P<0.05)and increased the expressions of Bax and cleaved caspase-3 in the rat models(P<0.01).Conclusion Quercetin improves pulmonary hypertension in rats possibly by promoting apoptosis through the HMGB1/RAGE/NF-κB pathway.

关 键 词：槲皮素 肺动脉高压 肺血管重构 

分 类 号：R544.1[医药卫生—心血管疾病]