GRK2–YAP signaling is implicated in pulmonary arterial hypertension development
Abstract. Background:. Pulmonary arterial hypertension (PAH) is characterized by excessive proliferation of small pulmonary arterial vascular smooth muscle cells (PASMCs), endothelial dysfunction, and extracellular matrix remodeling. G protein-coupled receptor kinase 2 (GRK2) plays an important rol...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wolters Kluwer
2024-04-01
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| Series: | Chinese Medical Journal |
| Online Access: | http://journals.lww.com/10.1097/CM9.0000000000002946 |
| _version_ | 1797224395096195072 |
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| author | Peng Ye Yunfei Deng Yue Gu Pengfei Liu Jie Luo Jiangqin Pu Jingyu Chen Yu Huang Nanping Wang Yong Ji Shaoliang Chen Rongman Jia Xiuyuan Hao |
| author_facet | Peng Ye Yunfei Deng Yue Gu Pengfei Liu Jie Luo Jiangqin Pu Jingyu Chen Yu Huang Nanping Wang Yong Ji Shaoliang Chen Rongman Jia Xiuyuan Hao |
| author_sort | Peng Ye |
| collection | DOAJ |
| description | Abstract.
Background:. Pulmonary arterial hypertension (PAH) is characterized by excessive proliferation of small pulmonary arterial vascular smooth muscle cells (PASMCs), endothelial dysfunction, and extracellular matrix remodeling. G protein-coupled receptor kinase 2 (GRK2) plays an important role in the maintenance of vascular tone and blood flow. However, the role of GRK2 in the pathogenesis of PAH is unknown.
Methods:. GRK2 levels were detected in lung tissues from healthy people and PAH patients. C57BL/6 mice, vascular smooth muscle cell-specific Grk2-knockout mice (Grk2ΔSM22), and littermate controls (Grk2flox/flox) were grouped into control and hypoxia mice (n = 8). Pulmonary hypertension (PH) was induced by exposure to chronic hypoxia (10%) combined with injection of the SU5416 (cHx/SU). The expression levels of GRK2 and Yes-associated protein (YAP) in pulmonary arteries and PASMCs were detected by Western blotting and immunofluorescence staining. The mRNA expression levels of Grk2 and Yes-associated protein (YAP) in PASMCs were quantified with real-time polymerase chain reaction (RT-PCR). Wound-healing assay, 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT) assay, and 5-Ethynyl-2′-deoxyuridine (EdU) staining were performed to evaluate the proliferation and migration of PASMCs. Meanwhile, the interaction among proteins was detected by immunoprecipitation assays.
Results:. The expression levels of GRK2 were upregulated in the pulmonary arteries of patients with PAH and the lungs of PH mice. Moreover, cHx/SU-induced PH was attenuated in Grk2ΔSM22 mice compared with littermate controls. The amelioration of PH in Grk2ΔSM22 mice was accompanied by reduced pulmonary vascular remodeling. In vitro study further confirmed that GRK2 knock-down significantly altered hypoxia-induced PASMCs proliferation and migration, whereas this effect was severely intensified by overexpression of GRK2. We also identified that GRK2 promoted YAP expression and nuclear translocation in PASMCs, resulting in excessive PASMCs proliferation and migration. Furthermore, GRK2 is stabilized by inhibiting phosphorylating GRK2 on Tyr86 and subsequently activating ubiquitylation under hypoxic conditions.
Conclusion:. Our findings suggest that GRK2 plays a critical role in the pathogenesis of PAH, via regulating YAP expression and nuclear translocation. Therefore, GRK2 serves as a novel therapeutic target for PAH treatment. |
| first_indexed | 2024-04-24T13:52:26Z |
| format | Article |
| id | doaj.art-508ed60ab8c64947beeaf3d76c5c3fe5 |
| institution | Directory Open Access Journal |
| issn | 0366-6999 2542-5641 |
| language | English |
| last_indexed | 2024-04-24T13:52:26Z |
| publishDate | 2024-04-01 |
| publisher | Wolters Kluwer |
| record_format | Article |
| series | Chinese Medical Journal |
| spelling | doaj.art-508ed60ab8c64947beeaf3d76c5c3fe52024-04-04T03:29:12ZengWolters KluwerChinese Medical Journal0366-69992542-56412024-04-01137784685810.1097/CM9.0000000000002946202404050-00009GRK2–YAP signaling is implicated in pulmonary arterial hypertension developmentPeng Ye0Yunfei Deng1Yue Gu2Pengfei Liu3Jie Luo4Jiangqin Pu5Jingyu Chen6Yu Huang7Nanping Wang8Yong Ji9Shaoliang Chen10Rongman JiaXiuyuan Hao1 Division of Cardiovascular Molecular Laboratory, Third Clinical College, Nanjing Medical University, Nanjing, Jiangsu 210006, China2 Division of Cardiovascular Laboratory, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, China2 Division of Cardiovascular Laboratory, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, China1 Division of Cardiovascular Molecular Laboratory, Third Clinical College, Nanjing Medical University, Nanjing, Jiangsu 210006, China2 Division of Cardiovascular Laboratory, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, China1 Division of Cardiovascular Molecular Laboratory, Third Clinical College, Nanjing Medical University, Nanjing, Jiangsu 210006, China4 Division of Pulmonary Surgery, Wuxi People’s Hospital, Nanjing Medical University, Wuxi, Jiangsu 300247, China5 Institute of Vascular Medicine, The Chinese University of Hong Kong, Hongkong 999077, China6 Health Science Center, East China Normal University, Shanghai 200241, China7 School of Pharmacy, Nanjing Medical University, Nanjing, Jiangsu 210004, China7 School of Pharmacy, Nanjing Medical University, Nanjing, Jiangsu 210004, ChinaAbstract. Background:. Pulmonary arterial hypertension (PAH) is characterized by excessive proliferation of small pulmonary arterial vascular smooth muscle cells (PASMCs), endothelial dysfunction, and extracellular matrix remodeling. G protein-coupled receptor kinase 2 (GRK2) plays an important role in the maintenance of vascular tone and blood flow. However, the role of GRK2 in the pathogenesis of PAH is unknown. Methods:. GRK2 levels were detected in lung tissues from healthy people and PAH patients. C57BL/6 mice, vascular smooth muscle cell-specific Grk2-knockout mice (Grk2ΔSM22), and littermate controls (Grk2flox/flox) were grouped into control and hypoxia mice (n = 8). Pulmonary hypertension (PH) was induced by exposure to chronic hypoxia (10%) combined with injection of the SU5416 (cHx/SU). The expression levels of GRK2 and Yes-associated protein (YAP) in pulmonary arteries and PASMCs were detected by Western blotting and immunofluorescence staining. The mRNA expression levels of Grk2 and Yes-associated protein (YAP) in PASMCs were quantified with real-time polymerase chain reaction (RT-PCR). Wound-healing assay, 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT) assay, and 5-Ethynyl-2′-deoxyuridine (EdU) staining were performed to evaluate the proliferation and migration of PASMCs. Meanwhile, the interaction among proteins was detected by immunoprecipitation assays. Results:. The expression levels of GRK2 were upregulated in the pulmonary arteries of patients with PAH and the lungs of PH mice. Moreover, cHx/SU-induced PH was attenuated in Grk2ΔSM22 mice compared with littermate controls. The amelioration of PH in Grk2ΔSM22 mice was accompanied by reduced pulmonary vascular remodeling. In vitro study further confirmed that GRK2 knock-down significantly altered hypoxia-induced PASMCs proliferation and migration, whereas this effect was severely intensified by overexpression of GRK2. We also identified that GRK2 promoted YAP expression and nuclear translocation in PASMCs, resulting in excessive PASMCs proliferation and migration. Furthermore, GRK2 is stabilized by inhibiting phosphorylating GRK2 on Tyr86 and subsequently activating ubiquitylation under hypoxic conditions. Conclusion:. Our findings suggest that GRK2 plays a critical role in the pathogenesis of PAH, via regulating YAP expression and nuclear translocation. Therefore, GRK2 serves as a novel therapeutic target for PAH treatment.http://journals.lww.com/10.1097/CM9.0000000000002946 |
| spellingShingle | Peng Ye Yunfei Deng Yue Gu Pengfei Liu Jie Luo Jiangqin Pu Jingyu Chen Yu Huang Nanping Wang Yong Ji Shaoliang Chen Rongman Jia Xiuyuan Hao GRK2–YAP signaling is implicated in pulmonary arterial hypertension development Chinese Medical Journal |
| title | GRK2–YAP signaling is implicated in pulmonary arterial hypertension development |
| title_full | GRK2–YAP signaling is implicated in pulmonary arterial hypertension development |
| title_fullStr | GRK2–YAP signaling is implicated in pulmonary arterial hypertension development |
| title_full_unstemmed | GRK2–YAP signaling is implicated in pulmonary arterial hypertension development |
| title_short | GRK2–YAP signaling is implicated in pulmonary arterial hypertension development |
| title_sort | grk2 yap signaling is implicated in pulmonary arterial hypertension development |
| url | http://journals.lww.com/10.1097/CM9.0000000000002946 |
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