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

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.