The Imatinib–miR-335-5p–ARHGAP18 Axis Attenuates PDGF-Driven Pathological Responses in Pulmonary Artery Smooth Muscle Cells

The proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) are key pathological features of vascular remodeling during pulmonary hypertension. Platelet-derived growth factor (PDGF) signaling is a major contributor to these processes. Given the importance of microRNA (miRNA) regulation in the PDGF signaling pathway in PASMCs, we hypothesized that imatinib, a tyrosine kinase inhibitor, modulates the expression levels of miRNAs responsive to PDGF signaling to ameliorate the PDGF signaling-induced PASMC phenotype. In this study, we investigated the role of miR-335-5p in PDGF signaling-induced PASMC proliferation and migration, as well as the involvement of imatinib in the regulatory network of miR-335-5p. miR-335-5p was identified as a critical negative regulator of PDGF signaling. Functional assays revealed that miR-335-5p significantly inhibits PASMC proliferation and migration. Through target prediction and validation, Rho GTPase Activating Protein 18 (ARHGAP18) was identified as a novel direct target of miR-335-5p. In addition, ARHGAP18 was found to play an essential role in regulating PASMC proliferation and migration. Although miR-335-5p was downregulated upon PDGF-BB stimulation, its expression was restored by imatinib. These findings highlight the important role of the imatinib-miR-335-5p-ARHGAP18 axis as a potential therapeutic target for pathological vascular remodeling.