首页|GRK2-YAP signaling is implicated in pulmonary arterial hypertension development

GRK2-YAP signaling is implicated in pulmonary arterial hypertension development

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  • 国家科技期刊平台
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Background:Pulmonary arterial hypertension(PAH)is characterized by excessive proliferation of small pulmonary arterial vas-cular 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(Grk2 △SM22),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 Grk2△SM22 mice compared with littermate controls.The amelioration of PH in Grk2△SM22 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 intensi-fied 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.

Pulmonary arterial hypertensionGRK2YAPPulmonary artery smooth muscle cellHypoxia

Peng Ye、Yunfei Deng、Yue Gu、Pengfei Liu、Jie Luo、Jiangqin Pu、Jingyu Chen、Yu Huang、Nanping Wang、Yong Ji、Shaoliang Chen

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Division of Cardiovascular Molecular Laboratory,Third Clinical College,Nanjing Medical University,Nanjing,Jiangsu 210006,China

Division of Cardiovascular Laboratory,Nanjing First Hospital,Nanjing Medical University,Nanjing,Jiangsu 210006,China

Division of Cardiology,Shanghai General Hospital,School of Medicine,Shanghai Jiao Tong University,Shanghai 200080,China

Division of Pulmonary Surgery,Wuxi People's Hospital,Nanjing Medical University,Wuxi,Jiangsu 300247,China

institute of Vascular Medicine,The Chinese University of Hong Kong,Hongkong 999077,China

Health Science Center,East China Normal University,Shanghai 200241,China

School of Pharmacy,Nanjing Medical University,Nanjing,Jiangsu 210004,China

Division of Cardiology,Nanjing First Hospital,Nanjing Medical University,Nanjing,Jiangsu 210006,China

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国家自然科学基金国家自然科学基金

NSFC 91639303NSFC 81770441

2024

10.1097/CM9.0000000000002946

中华医学杂志(英文版)
中华医学会

中华医学杂志(英文版)

CSTPCD
影响因子：0.838
ISSN：0366-6999
年,卷(期)：2024.137(7)
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