Abstract 16380: Bosentan Inhibits Proliferation of Cells Isolated from Patients with Chronic Thromboembolic Pulmonary Hypertension
Background: Chronic thromboembolic pulmonary hypertension (CTEPH) develops in about 4% of patients with acute pulmonary thromboembolism. About 50% of CTEPH patients are inoperable or suffering from persistant pulmonary hypertension after pulmonary thromboendarterectomy. There are emerging evidences that support efficacy of oral dual endothelin antagonist, bosentan, in clinical settings. Since little is known about the mechanisms by which CTEPH develops, it is not clear how this drug effects on pulmonary vasculature in CTEPH patients. We have reported that platelet-derived growth factor (PDGF) plays an important role in pulmonary vascular remodeling in CTEPH as well as in idiopathic pulmonary arterial hypertension (IPAH). We aimed to study whether bosentan inhibits PDGF-induced cell proliferation and PDGF signaling pathway.
Methods and Results: We isolated cells (CTEPH cells) from pulmonary arteries from patients with CTEPH. Pulmonary artery smooth muscle cells (PASMC) were isolated from patients with IPAH and normal PASMC were also used as control. Cells were cultured and treated with bosentan (from 10−4 to 10−8 M) concomitant with PDGF (10 ng/ml) for 24 hours. Bosentan (10−5 and 10−4 M) significantly inhibited PDGF-induced augmentation of thymidine uptake in CTEPH cells (Figure). PDGF-induced proliferation of PASMC from patients with IPAH and normal subjects were also significantly inhibited. However, phosphorylation of neither Akt nor ERK was attenuated by bosentan treatment.
Conclusions: The data suggest that bosentan successfully inhibits PDGF-induced proliferation of CTEPH cells. This effect was not caused by direct inhibition of the downstream of PDGF signaling. In conclusion, we demonstrated direct evidence that bosentan can be used as a therapeutic option for inoperable CTEPH patients. Further study is needed to understand the mechanism of this effect.
- © 2010 by American Heart Association, Inc.