Abstract 13830: Imatinib in the Presence of Platelet-derived Growth Factor Inhibits Proliferation 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 an inappropriate increase in 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 of PASMCs obtained from patients with IPAH, and we investigated whether imatinib induces apoptosis of PASMCs.
Methods and Results: PASMCs were obtained from 8 patients with IPAH undergoing lung transplantation. Treatment with imatinib (0.1 to 10 μg/mL) inhibited PDGF-BB (10 ng/mL)-induced proliferation of PASMCs from IPAH patients in a dose-dependent manner as assessed by 3H-thymidine incorporation. Western blot analysis revealed that PDGF-BB decreased the expression of the cyclin-dependent kinase inhibitor p27Kip1 in IPAH-PASMCs and that imatinib significantly increased the expression of p27Kip1 in IPAH-PASMCs compared with treatment with PDGF-BB. TUNEL and caspase-3,7 assays and transmission electron microscopic analysis revealed that imatinib (1 μg/mL) alone did not induce apoptosis in IPAH-PASMCs but that imatinib in the presence of PDGF had a proapoptotic effect on IPAH-PASMCs (Fig 1). PDGF-BB induced phosphorylation of Akt at 15 and 60 minutes, and Akt phosphorylation was inhibited by imatinib. Akt-I-1/2 (1 μmol/L), an Akt inhibitor, significantly inhibited PDGF-induced proliferation of IPAH-PASMCs as assessed by 3H-thymidine incorporation. Akt-I-1/2 in the presence of PDGF-BB significantly increased TUNEL-positive cells and caspase-3,7-positive cells in IPAH-PASMCs compared with the control condition (Fig 2). Thus, Akt-I-1/2 could mimic the effects of imatinib on PASMCs.
Conclusions: Modulation of PDGF signaling such as p27Kip1 and Akt by imatinib causes anti-proliferative and pro-apoptotic effects in IPAH-PASMCs.
- © 2010 by American Heart Association, Inc.