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A novel PDGFR inhibitor WQ-C-401 prevents pulmonary vascular remodeling in rats with monocrotaline-induced pulmonary arterial hypertension

文献类型：期刊论文

作者Huang, Wen; Zhou, Hong1; He, Yiting; Wang, Aoli; Wang, Beilei; Chen, Yongfei3,4; Liu, Chenyang2; Wang, Hong2; Xie, Weiping2; Kong, Hui2
刊名EXPERIMENTAL CELL RESEARCH
出版日期2024-08-01
卷号441
关键词WQ-C-401 Pulmonary arterial hypertension Pulmonary vascular remodeling Platelet-derived growth factor receptor Smooth muscle cells
ISSN号0014-4827
DOI10.1016/j.yexcr.2024.114154
通讯作者Xie, Weiping(wpxie@njmu.edu.cn) ; Kong, Hui(konghui@njmu.edu.cn)
英文摘要Platelet-derived growth factor (PDGF) is one of the most important cytokines associated with pulmonary vascular remodeling in pulmonary arterial hypertension (PAH). PDGF receptor (PDGFR) inhibition exerted therapeutic effects on PAH in clinical trials, but serious side effects warrant the withdrawal of existing drugs. In this study, a novel highly selective PDGFR inhibitor WQ-C-401 was developed, and its effects on PDGFR signaling pathway and pulmonary vascular remodeling in PAH were investigated. Cell proliferation assays and Western blot analysis of PDGFR alpha/beta phosphorylation showed that WQ-C-401 inhibited PDGFR-mediated cell proliferation assay and suppressed PDGFR phosphorylation in a concentration-dependent manner. DiscoverX's KinomeScanTM technology confirmed the good kinome selectivity of WQ-C-401 (S score (1) of PDGFR = (0.01)). In monocrotaline (MCT)-induced PAH rats, intragastric administration of WQ-C-401 (25, 50, 100 mg/kg/d) or imatinib (50 mg/ kg/d, positive control) significantly decreased right ventricular systolic pressure (RVSP). Histological analysis demonstrated that WQ-C-401 inhibited pulmonary vascular remodeling by reducing muscularization and fibrosis, as well as alleviated right ventricular hypertrophy in MCT-treated rats. In addition, WQ-C-401 suppressed MCT-induced cell hyperproliferation and CD68+ macrophage infiltration around the pulmonary artery. In vitro, WQ-C-401 inhibited PDGF-BB-induced proliferation and migration of human pulmonary arterial smooth muscle cells (PASMCs). Moreover, Western blot analysis showed that WQ-C-401 concertration-dependently inhibited PDGF-BB-induced phosphorylation of ERK1/2 and PDGFR beta Y751, decreased collagen I synthesis and increased alpha smooth muscle actin (alpha-SMA) expression in PASMCs. Collectively, our results suggest that WQ-C401 is a selective and potent PDGFR inhibitor which could be a promising drug for the therapeutics of PAH by preventing pulmonary vascular remodeling.
WOS关键词MUSCLE-CELL DIFFERENTIATION ; SMOOTH-MUSCLE ; RECEPTOR ; IMATINIB ; PHOSPHORYLATION ; INFLAMMATION ; PATHOLOGY ; PATHWAYS ; THERAPY ; SITE
资助项目Jiangsu Provincial Medical Innovation Center[CXZX202206] ; Key Project of National Science & Technology for Infectious Diseases of China[2018ZX10722301]
WOS研究方向Oncology ; Cell Biology
语种英语
WOS记录号WOS:001273576000001
出版者ELSEVIER INC
资助机构Jiangsu Provincial Medical Innovation Center ; Key Project of National Science & Technology for Infectious Diseases of China
源URL[http://ir.hfcas.ac.cn:8080/handle/334002/137283]  
专题中国科学院合肥物质科学研究院
通讯作者Xie, Weiping; Kong, Hui
作者单位1.Nanjing Med Univ, Affiliated Wuxi Peoples Hosp, Wuxi Peoples Hosp, Wuxi Med Ctr,Dept Pulm & Crit Care Med, Wuxi 214023, Jiangsu, Peoples R China
2.Nanjing Med Univ, Affiliated Hosp 1, Jiangsu Prov Hosp, Dept Pulm & Crit Care Med, Nanjing 210029, Jiangsu, Peoples R China
3.Chinese Acad Sci, Hefei Canc Hosp, Hefei 230031, Anhui, Peoples R China
4.Chinese Acad Sci, Inst Hlth & Med Technol, Hefei Inst Phys Sci, Anhui Prov Key Lab Med Phys & Technol, Hefei 230031, Anhui, Peoples R China
推荐引用方式
GB/T 7714		 Huang, Wen,Zhou, Hong,He, Yiting,et al. A novel PDGFR inhibitor WQ-C-401 prevents pulmonary vascular remodeling in rats with monocrotaline-induced pulmonary arterial hypertension[J]. EXPERIMENTAL CELL RESEARCH,2024,441.
APA Huang, Wen.,Zhou, Hong.,He, Yiting.,Wang, Aoli.,Wang, Beilei.,...&Kong, Hui.(2024).A novel PDGFR inhibitor WQ-C-401 prevents pulmonary vascular remodeling in rats with monocrotaline-induced pulmonary arterial hypertension.EXPERIMENTAL CELL RESEARCH,441.
MLA Huang, Wen,et al."A novel PDGFR inhibitor WQ-C-401 prevents pulmonary vascular remodeling in rats with monocrotaline-induced pulmonary arterial hypertension".EXPERIMENTAL CELL RESEARCH 441(2024).

入库方式： OAI收割

来源：合肥物质科学研究院

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