钙敏感受体在肺动脉高压小鼠肺静脉重塑中的作用及机制研究  

A study on the role and mechanism of calcium-sensing receptor in pulmonary venous remodeling in pulmonary hypertension mice

作　　者：高晓华 薛燕 莫秋弟 袁泓 彭公永[1] GAO Xiaohua;XUE Yan;MO Qiudi;YUAN Hong;PENG Gongyong(Department of Internal Medicine and Department of Pulmonary and Critical Care Medicine,the First Affiliated Hospital of Guangzhou Medical University Hengqin Hospital,Department of Geriatric Medicine,the First Affiliated Hospital of Guangzhou Medical University,National Key Laboratory of Respiratory Diseases,National Center for Respiratory Medicine,National Clinical Research Center for Respiratory Diseases,Guangzhou Institute of Respiratory Health,Guangzhou 510120,China;Department of Pulmonary and Critical Care Medicine,Shenzhen People′s Hospital,Shenzhen 518020,China;Department of Pulmonary and Critical Care Medicine,the Second Affiliated Hospital of Guangzhou Medical University,Guangzhou 510260,China)

机构地区：[1]广州医科大学附属第一医院横琴医院内科及呼吸与危重症医学科,广州医科大学附属第一医院老年科,呼吸疾病全国重点实验室,国家呼吸医学中心,国家呼吸系统疾病临床医学研究中心,广州呼吸健康研究院,广州510120 [2]深圳市人民医院呼吸与危重症医学科,深圳518020 [3]广州医科大学附属第二医院呼吸与危重症医学科,广州510260

出　　处：《中国临床新医学》2025年第1期6-11,共6页CHINESE JOURNAL OF NEW CLINICAL MEDICINE

基　　金：国家自然科学基金项目(编号:82170056);广东省自然科学基金项目(编号:2021A1515011024);广州市科技计划市校联合资助项目(编号:202201020404)。

摘　　要：目的研究钙敏感受体(CaSR)在肺动脉高压(PH)小鼠肺静脉重塑中的作用及机制。方法选用C57/BL6小鼠28只,随机均分为常氧(Nor)组、常氧+NPS2143(Nor+NPS)组、低氧联合SU5416(HySu)组、低氧联合SU5416+NPS2143(HySu+NPS)组,每组7只。通过低氧(10%O 2)条件下饲养加皮下注射SU5416的方法构建PH小鼠模型。利用血流动力学测定和右心室肥厚指数(RVHI)分析评估PH,应用Weigert弹力纤维染色、HE染色、α-SMA免疫组化染色和CaSR免疫组化染色评估血管重塑。通过Western blot检测肺静脉CaSR、经典瞬时受体电位蛋白(TRPC)6及TRPC4的表达水平。结果通过低氧联合SU5416成功构建PH小鼠模型。HySu组小鼠右心室收缩压(RVSP)和RVHI显著高于Nor组。PH小鼠的远端肺静脉发生血管重塑,但近端肺静脉无血管重塑。PH小鼠的CaSR、TRPC6表达水平较Nor组显著上调(P<0.05),而TRPC4表达与Nor组比较无显著差异(P>0.05)。加入NPS2143干预后,HySu+NPS组小鼠的RVSP和RVHI显著低于HySu组(P<0.05),并且NPS2143可显著缓解低氧联合SU5416诱导的小鼠远端肺静脉重塑,并下调PH小鼠远端肺静脉CaSR和TRPC6表达(P<0.05)。结论CaSR在PH小鼠远端肺静脉重塑中发挥核心作用,低氧联合SU5416可能通过上调远端肺静脉平滑肌CaSR表达而引起TRPC6表达上调导致肺静脉重塑。Objective To study the role and mechanism of calcium-sensing receptor(CaSR)in pulmonary venous remodeling in pulmonary hypertension(PH)mice.Methods A total of 28 C57/BL6 mice were randomly divided into normoxia(Nor)group,normoxia+NPS2143(Nor+NPS)group,hypoxia combined with SU5416(HySu)group and hypoxia combined with SU5416+NPS2143(HySu+NPS)group,with 7 mice in each group.A PH mouse model was developed by feeding under hypoxic(10%O 2)condition and injecting SU5416 subcutaneously.PH was assessed by using hemodynamic measurement and right ventricular hypertrophy index(RVHI)analysis,and vascular remodeling was assessed by using Weigert′s elastin staining,hematoxylin and eosin(HE)staining,alpha-smooth muscle actin(α-SMA)immunohistochemical staining,and CaSR immunohistochemical staining.The expression levels of CaSR,canonical transient receptor potential protein(TRPC)6 and TRPC4 in pulmonary vein were detected by Western blot.Results The PH mouse model was successfully developed by hypoxia combined with SU5416.The right ventricular systolic pressure(RVSP)and RVHI of mice in the HySu group were significantly higher than those in the Nor group.The distal pulmonary veins of PH mice underwent vascular remodeling,while the proximal pulmonary veins of PH mice showed no vascular remodeling.The expression levels of CaSR and TRPC6 in the PH mice were significantly up-regulated compared with those in the mice of the Nor group(P<0.05),but there was no significant difference in TRPC4 expression between the PH mice and the mice of the Nor group(P>0.05).After the intervention with NPS2143,the RVSP and RVHI of mice in the HySu+NPS group were significantly lower than those in the HySu group(P<0.05),and NPS2143 could significantly alleviate the distal pulmonary venous remodeling induced by hypoxia combined with SU5416,and down-regulated the expressions of CaSR and TRPC6 in the distal pulmonary veins of PH mice(P<0.05).Conclusion CaSR plays a core role in the remodeling of distal pulmonary veins in PH mice.Hypoxia combined with SU541

关 键 词：钙敏感受体 经典瞬时受体电位蛋白 肺动脉高压 肺静脉重塑 

分 类 号：R544.16[医药卫生—心血管疾病]