FAP Promotes Pulmonary Artery Hypertension via Activation of the PTEN/PI3K/Akt Pathway.

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.