Abstract 5663: Imatinib Inhibits Proliferation and Migration and Induces Apoptosis in Pulmonary Artery Smooth Muscle Cells From Patients With Idiopathic Pulmonary Arterial Hypertension
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 3H-thymidine incorporation (normal: 179±45 vs. IPAH: 310±31 % of counts before PDGF, P<0.05). After treatment with imatinib (0.1 and 1 μg/mL), PDGF-induced cell proliferation of PASMCs from IPAH patients decreased by 51% and 90 % respectively (PDGF vs PDGF+imatinib (0.1 and 1 μg/mL): P<0.001). Western blot analysis revealed that imatinib (1 μg/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 μg/mL) inhibited PDGF-induced migration (P<0.0001). TUNEL assay revealed that imatinib (1 μg/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.