Zhu Minghui, Xu Fei, Zhu Le, Chen Qianqian, Jiang Xiaomin, Pan Chang, Yu Wande, Zhang Hang
Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China.
Department of Critical Care Medicine, Lianshui County Peoples Hospital, Huaian 223400, China.
J Cardiovasc Pharmacol. 2025 Jul 17. doi: 10.1097/FJC.0000000000001735.
Pulmonary arterial hypertension (PAH) is a severe disease characterized by significant pulmonary vascular remodeling and right ventricular dysfunction. Activated fibroblasts can induce collagen deposition around blood vessels, thereby promoting vascular hardening and PAH development. Fibroblast activation protein (FAP) is a proline-specific serine protease expressed in active fibroblasts that is closely associated with tissue remodeling, inflammation, fibrosis, tumor growth, and cellular proliferation. However, whether FAP is linked to PAH has not yet been addressed. This study aimed to investigate the potential role of FAP in PAH pathogenesis. In animal models of PAH, we found that FAP expression levels were higher both in vivo and in vitro than in the control group. And FAP inhibitors alleviated pulmonary vascular remodeling and right ventricular function in vivo PAH model. To explain the elevated expression of FAP in PAH, we screened the transcription factor Egr1 of FAP through the databases GTRD and Human TFDB, and demonstrated that the transcriptional activity of Egr1 binds to the FAP promoter region and regulates FAP by chromatin immunoprecipitation (ChIP) assay and the dual-luciferase reporter gene assay. Subsequently, we demonstrated that FAP promotes the activation of pulmonary arterial adventitial fibroblasts (PAAFs) by enhancing their proliferation, migration, and transformation into muscle fibroblasts. Furthermore, FAP mechanistically affects the PTEN/PI3K/Akt signaling pathway, which is a classical signaling pathway that regulates fibroblast proliferation, migration, and invasion. In summary, FAP plays a crucial role in activating PAAFs and may be a potential therapeutic target for patients with PAH.
肺动脉高压（PAH）是一种严重疾病，其特征为显著的肺血管重塑和右心室功能障碍。活化的成纤维细胞可诱导血管周围胶原蛋白沉积，从而促进血管硬化和PAH的发展。成纤维细胞活化蛋白（FAP）是一种在活化的成纤维细胞中表达的脯氨酸特异性丝氨酸蛋白酶，与组织重塑、炎症、纤维化、肿瘤生长和细胞增殖密切相关。然而，FAP是否与PAH有关尚未得到研究。本研究旨在探讨FAP在PAH发病机制中的潜在作用。在PAH动物模型中，我们发现体内和体外FAP表达水平均高于对照组。并且FAP抑制剂可减轻体内PAH模型中的肺血管重塑和右心室功能。为了解释PAH中FAP表达升高的原因，我们通过数据库GTRD和Human TFDB筛选了FAP的转录因子Egr1，并通过染色质免疫沉淀（ChIP）试验和双荧光素酶报告基因试验证明Egr1的转录活性与FAP启动子区域结合并调节FAP。随后，我们证明FAP通过增强肺动脉外膜成纤维细胞（PAAFs）的增殖、迁移以及向肌成纤维细胞的转化来促进其活化。此外，FAP在机制上影响PTEN/PI3K/Akt信号通路，这是一条调节成纤维细胞增殖、迁移和侵袭的经典信号通路。总之，FAP在激活PAAFs中起关键作用，可能是PAH患者的潜在治疗靶点。
