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

doi:10.3877/cma.j.issn.1674-6902.2023.04.002

Abstract

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.

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

Jie Huang, Yu Xia, Yanjiao Jiang, Yun Liu. Effects of GPR146 on vascular remodeling in mice with pulmonary hypertension via P-JNK pathway[J]. Chinese Journal of Lung Diseases(Electronic Edition), 2023, 16(04): 460-465.

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Figures/Tables 7

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