Abstract 5663: Imatinib Inhibits Proliferation and Migration and Induces Apoptosis in Pulmonary Artery Smooth Muscle Cells From Patients With Idiopathic Pulmonary Arterial Hypertension

Abstract

Background : Idiopathic pulmonary arterial hypertension (IPAH) is characterized by inappropriate increase of pulmonary artery smooth muscle cells (PASMCs). We assessed the inhibitory effects of imatinib, a platelet-derived growth factor (PDGF)-receptor tyrosine kinase inhibitor, on PDGF-induced proliferation and migration of PASMCs obtained from patients with IPAH, and investigated whether imatinib induces apoptosis of PASMCs. Methods and Results : PASMCs were obtained from 7 patients with IPAH undergoing lung transplantation. PDGF (10 ng/mL) stimulation caused a higher growth rate of PASMCs from patients with IPAH than that of normal control PASMCs (n=6) as assessed by 3 H-thymidine incorporation (normal: 179±45 vs. IPAH: 310±31 % of counts before PDGF, P <0.05). After treatment with imatinib (0.1 and 1 μ g/mL), PDGF-induced cell proliferation of PASMCs from IPAH patients decreased by 51% and 90 % respectively (PDGF vs PDGF+imatinib (0.1 and 1 μ g/mL): P <0.001). Western blot analysis revealed that imatinib (1 μ g/mL) increased the expression of cyclin-dependent kinase inhibitor p27 in IPAH-PASMCs compared with treatment with PDGF (53%; PDGF vs. PDGF+imatinib, P <0.005). A time-lapse system revealed that PDGF increased the migration distance of IPAH-PASMCs compared to that of normal PASMCs ( P <0.0001), and imatinib (1 μ g/mL) inhibited PDGF-induced migration ( P <0.0001). TUNEL assay revealed that imatinib (1 μ g/mL) alone did not induce apoptosis in IPAH-PASMCs, but combination of imatinib and PDGF increased apoptotic cells (Figure ). Conclusions: Inhibition of PDGF signaling by imatinib may become a useful molecular-targeted therapy for IPAH. Figure. Effect of imatinib on apoptosis of PASMICs in Tunnel assay.