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Pro-apoptotic effects of imatinib on PDGF-stimulated pulmonary artery smooth muscle cells from patients with idiopathic pulmonary arterial hypertension
International Journal of Cardiology, 08/17/2012
Clinical Article
Nakamura K et al. – Imatinib has anti–proliferative and pro–apoptotic effects on idiopathic pulmonary arterial hypertension (IPAH)–pulmonary artery smooth muscle cells (PASMCs) stimulated with platelet–derived growth factor (PDGF). The inhibitory effect of imatinib on Akt phosphorylation induced by PDGF plays an important role in the pro–apoptotic effect.
Methods- PASMCs were obtained from 8 patients with IPAH undergoing lung transplantation.
- Cellular proliferation was assessed by 3H–thymidine incorporation.
- Pro–apoptotic effects of imatinib were examined using TUNEL and caspase–3,7 assays and using transmission electron microscopy.
- Treatment with imatinib (0.1 to 10μg/mL) significantly inhibited PDGF–BB (10ng/mL)–induced proliferation of PASMCs from IPAH patients.
- Imatinib (1μg/mL) did not induce apoptosis in quiescent IPAH–PASMCs, but it had a pro–apoptotic effect on IPAH–PASMCs stimulated with PDGF–BB.
- Imatinib did not induce apoptosis in normal control PASMCs with or without PDGF–BB stimulation.
- PDGF–BB induced phosphorylation of Akt at 15min, and Akt phosphorylation was inhibited by imatinib in IPAH–PASMCs.
- Akt–I–1/2 (1μmol/L), an Akt inhibitor, in the presence of PDGF–BB significantly increased apoptotic cells compared with the control condition.
- Thus, Akt–I–1/2 could mimic the effects of imatinib on PASMCs.