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《中华肺部疾病杂志》[ISSN:1006-6977/CN:61-1281/TN]

卷:

期数:

2023年04期

页码:

460-465

栏目:

论著

出版日期:

2023-08-20

文章信息/Info

Title:

Effects of GPR146 on vascular remodeling in mice with pulmonary hypertension via P-JNK pathway

作者:

黄 杰¹; 夏 瑜²; 姜艳娇²; 刘 云¹

222061 连云港,徐州医科大学附属连云港医院药学部¹、呼吸内科²

Author(s):

Huang Jie¹;  Xia Yu²;  Jiang Yanjiao²;  Liu Yun¹.

¹Department of Pharmacy; ²Respiratory Medicine, The Affiliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang 222061, China

关键词:

G蛋白偶联受体146;  血管重塑;  肺动脉平滑肌细胞;  磷酸化氨基末端蛋白激酶

Keywords:

Orphan G protein-coupled receptor 146;  Vascular remodeling;  Pulmonary artery smooth muscle cells;  Phosphorylated c-Jun N-terminal kinase

分类号:

R543.2

DOI:

10.3877/cma.j.issn.1674-6902.2023.04.002

摘要:

目的 分析G蛋白偶联受体146(orphan G protein-coupled receptor 146, GPR146)经磷酸化氨基末端蛋白激酶(phosphorylated c-Jun N-terminal kinase, P-JNK)通路对肺动脉高压(pulmonary hypertension, PH)肺血管重构(pulmonary vascular remodeling, PVR)致肺血管压力升高的影响。方法 构建PH模型,采用SD大鼠10只,分为对照组和SuHx组,每组5只; 采用小鼠20只,分为Control组、SuHx组、SuHx+SiNC组、SuHx+SiGPR146组,共4组。测量每组右心室收缩压(right ventricular systolic pressure, RVSP)和右心室肥厚指数(right ventricular hypertrophy index, RVHI)。免疫荧光(immunofluorescence, IFC)染色观察GPR146表达,免疫印迹检测GPR146、P-JNK与增殖细胞抗原(proliferating cell nuclear antigen, PCNA)表达。结果 与Control组相比,SuHx组大鼠肺组织GPR146升高(P<0.05,t=4.742)。GPR146主要在α-actin染色血管中膜层平滑肌细胞表达; SuHx组小鼠肺组织GPR146升高,SuHx+SiGPR146组GPR146比SuHx+SiNC组低(P<0.05,F=8.576)。SuHx组小鼠肺组织P-JNK与PCNA升高,干扰GPR146后P-JNK与PCNA表达降低(P<0.05,F=6.048,25.55); SuHx组小鼠RVSP和RVHI高于Control组,干扰GPR146后SuHx+SiGPR146组小鼠RVSP和RVHI低于SuHx+SiNC组; SuHx组小鼠肺血管壁厚度比Control组厚; 敲除GPR146后,SuHx+siGPR146组小鼠肺血管壁厚度小于SuHx+siNC组(P<0.05,F=4.106); HYP+SiGPR146组PASMCs中GPR146下调(P<0.05,F=6.907),与SiNC组相比,HYP+SiNC组PASMCs中P-JNK与PCNA表达上调,敲除GPR146后HYP+SiGPR146组中P-JNK与PCNA蛋白相较于HYP+SiNC组下调(P<0.05,F=7.436,33.68)。结论 GPR146经P-JNK通路促进肺动脉平滑肌细胞(PASMCs)增殖,加剧PH进展,可为预防和治疗PH可行靶点。

Abstract:

Objective To investigate the effect of G protein-coupled receptor 146(GPR146)on pulmonary vascular pressure elevation induced by pulmonary vascular remodeling(PVR)in pulmonary hypertension(PH)via phosphorylated c-Jun N-terminal kinase(P-JNK)pathway. Methods Ten SD rats were used to establish PH models and were divided into control group and SuHx group, with 5 rats in each group. Twenty mice were divided into Control group, SuHx group, SuHx+SiNC group and SuHx+SiGPR146 group. Right ventricular systolic pressure(RVSP)and right ventricular hypertrophy index(RVHI)were measured. The expression of GPR146 was detected by immunofluorescence(IFC)staining, and the expressions of GPR146, P-JNK and proliferating cell nuclear antigen(PCNA)were detected by Western Blot. Results Compared with Control group, GPR146 in lung tissue of SuHx group was increased(P<0.05, t=4.742). GPR146 was mainly expressed in α-actin stained vascular mesenchyme smooth muscle cells. GPR146 in SuHx group was increased, and GPR146 in SuHx+SiGPR146 group was lower than SuHx+SiNC group(P<0.05, F=8.576). The expression of P-JNK and PCNA in lung tissue of SuHx group was increased, and the expression of P-JNK and PCNA was decreased after interference with GPR146(P<0.05, F=6.048,25.55); The RVSP and RVHI of SuHx group were higher than those of Control group, and the RVSP and RVHI of SuHx+SiGPR146 group were lower than those of SuHx+SiNC group after interference with GPR146. The pulmonary vascular wall thickness in SuHx group was thicker than that in Control group. After GPR146 was knocked out, the pulmonary vascular wall thickness in SuHx+siGPR146 group was lower than that in SuHx+siNC group(P<0.05, F=4.106); GPR146 in PASMCs of HYP+SiGPR146 group was down-regulated(P<0.05, F=6.907). Compared with SiNC group, P-JNK and PCNA expressions in PASMCs of HYP+SiNC group were up-regulated. After GPR146 knockout, P-JNK and PCNA proteins in HYP+SiGPR146 group were down-regulated compared with those in HYP+SiNC group(P<0.05, F=7.436,33.68). Conclusion GPR146 promotes the proliferation of pulmonary artery smooth muscle cells(PASMCs)through the P-JNK pathway and aggravates the progression of PH, which can be a feasible target for the prevention and treatment of PH.

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备注/Memo

备注/Memo:

收稿日期:2023-03-05)
基金项目: 国家自然科学基金资助项目(31871155)
通信作者: 刘 云, Email: yunliu211315@163.com

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更新日期/Last Update: 2023-08-20