2. Academic Validation
  3. A novel PDGFR inhibitor WQ-C-401 prevents pulmonary vascular remodeling in rats with monocrotaline-induced pulmonary arterial hypertension

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

  • Exp Cell Res. 2024 Aug 1;441(1):114154. doi: 10.1016/j.yexcr.2024.114154.
Wen Huang 1,  Hong Zhou 2,  Yiting He 1,  Aoli Wang 3,  Beilei Wang 3,  Yongfei Chen 3,  Chenyang Liu 1,  Hong Wang 1,  Weiping Xie 4,  Hui Kong 5
Affiliations

Affiliations

  • 1 Department of Pulmonary & Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing 210029, Jiangsu, PR China.
  • 2 Department of Pulmonary & Critical Care Medicine, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi 214023, Jiangsu, PR China.
  • 3 Anhui Province Key Laboratory of Medical Physics & Technology, Institute of Health & Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, Anhui, PR China; Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei 230031, Anhui, PR China.
  • 4 Department of Pulmonary & Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing 210029, Jiangsu, PR China. Electronic address: wpxie@njmu.edu.cn.
  • 5 Department of Pulmonary & Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing 210029, Jiangsu, PR China. Electronic address: konghui@njmu.edu.cn.
PMID: 38996959 DOI: 10.1016/j.yexcr.2024.114154
Abstract

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 PDGFRα/β 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 PDGFRβ Y751, decreased collagen Ⅰ synthesis and increased alpha smooth muscle actin (α-SMA) expression in PASMCs. Collectively, our results suggest that WQ-C-401 is a selective and potent PDGFR Inhibitor which could be a promising drug for the therapeutics of PAH by preventing pulmonary vascular remodeling.

Keywords

Platelet-derived growth factor receptor; Pulmonary arterial hypertension; Pulmonary vascular remodeling; Smooth muscle cells; WQ-C-401.

Figures
Products