Abstract 2618: Bone Morphogenic Protein-9 Stimulates Endothelin-1 Synthesis by Human Pulmonary Microvascular Endothelial Cells: A Possible Contributor to the Pathogenesis of Pulmonary Arterial Hypertension
Pulmonary arterial hypertension (PAH) is thought to be related to progressive obliteration of the pulmonary microvasculature. Endothelial proliferation and dysfunction is a central process, and increased levels of the potent endothelial-derived vasoconstrictor and mitogen, endothelin-1 (ET-1) have been described. It is not known what triggers these increased ET-1 levels. With the description of mutations in receptors for bone morphogenic proteins (BMP) and other members of the TGF-beta family of proteins as causative events in hereditary forms of PAH, we hypothesized that BMPs might modulate ET-1 synthesis. Recently, BMP-9, which acts via the type-1 TGF-beta receptor activin-like kinase 1 (ALK-1), has been identified as a potent regulator of endothelial proliferation and migration. We therefore studied the effects of BMP-9 on ET-1 in-vitro production by human lung microvascular endothelial cells (HLMVEC), the cell implicated in the pathogenesis of PAH. HLMVEC were cultured to confluence in EGM-2MV medium and then BMP-9 (0 –100 ng/ml) was added to the medium for 24 and 48 hours. All concentrations increased ET-1 production at both time points, with 10 ng/ml resulting in a 99% increase versus controls at 24 hours and 104% at 48 hours (all p<0.001). Addition of SB-431542 (10 uM) a specific inhibitor of the kinase activity of ALK-5 significantly reduced the 48 hour ET-1 synthesis provoked by BMP-9, with a 41% decrease for 1 ng/ml BMP-9 but only a 9% reduction for 10 and 100ng/ml BMP-9. In conclusion, this is the first identification of BMP-9 as a potent stimulator of ET-1 production by HLMVEC. Although the actions of BMP-9 are thought to be through ALK-1, there may be a component of interaction with ALK-5, or ALK-5 may have cross-talk with ALK-1. ALK-5 inhibitors such as SB-431542 can reduce BMP-9 mediated ET-1 production and might ultimately have therapeutic benefit for PAH.