Department of Pulmonary & Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing 210029, Jiangsu, PR China.
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.
Exp Cell Res. 2024 Aug 1;441(1):114154. doi: 10.1016/j.yexcr.2024.114154. Epub 2024 Jul 10.
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.
血小板衍生生长因子 (PDGF) 是与肺动脉高压 (PAH) 肺血管重构相关的最重要细胞因子之一。在临床试验中，PDGF 受体 (PDGFR) 抑制剂对 PAH 发挥了治疗作用，但严重的副作用导致现有药物被撤回。在这项研究中，开发了一种新型高度选择性 PDGFR 抑制剂 WQ-C-401，并研究了其对 PDGFR 信号通路和 PAH 肺血管重构的影响。细胞增殖测定和 PDGFRα/β磷酸化的 Western blot 分析表明，WQ-C-401 抑制 PDGFR 介导的细胞增殖测定，并以浓度依赖性方式抑制 PDGFR 磷酸化。DiscoverX 的 KinomeScanTM 技术证实了 WQ-C-401 的良好激酶选择性 (S 分数 (1) PDGFR = (0.01))。在野百合碱 (MCT) 诱导的 PAH 大鼠中，胃内给予 WQ-C-401(25、50、100mg/kg/d)或伊马替尼 (50mg/kg/d，阳性对照)可显著降低右心室收缩压 (RVSP)。组织学分析表明，WQ-C-401 通过减少肌化和纤维化抑制肺血管重构，并减轻 MCT 处理大鼠的右心室肥大。此外，WQ-C-401 抑制 MCT 诱导的细胞过度增殖和肺动脉周围 CD68 巨噬细胞浸润。在体外，WQ-C-401 抑制 PDGF-BB 诱导的人肺动脉平滑肌细胞 (PASMCs) 增殖和迁移。此外，Western blot 分析表明，WQ-C-401 浓度依赖性地抑制 PDGF-BB 诱导的 ERK1/2 和 PDGFRβ Y751 磷酸化，减少胶原 Ⅰ 合成并增加 PASMCs 中的α平滑肌肌动蛋白 (α-SMA) 表达。总之，我们的结果表明，WQ-C-401 是一种选择性和有效的 PDGFR 抑制剂，通过防止肺血管重构，可能成为治疗 PAH 的有前途的药物。
