BMPR2 mutation alters the lung macrophage endothelin-1 cascade in a mouse model and patients with heritable pulmonary artery hypertension.

Talati M, West J, Blackwell TR, Loyd JE, Meyrick B. BMPR2 mutation alters the lung macrophage endothelin-1 cascade in a mouse model and patients with heritable pulmonary artery hypertension. Am J Physiol Lung Cell Mol Physiol 299: L363-L373, 2010. First published June 18, 2010; doi:10.1152/ajplung.00295.2009.-Macrophage derived-endothelin-1 (ET-1) has been suggested to contribute to a number of chronic lung diseases. Whether the ET-1 cascade from non-vascular sources (inflammatory cells) also contributes to pulmonary artery hypertension (PAH) and in particular to heritable PAH (HPAH) with known bone morphogenetic protein type 2 receptor (BMPR2) mutations is not known. We tested this notion using bone marrow-derived macrophages (BMDM; precursors of tissue macrophages) isolated from ROSA26rtTAXTetO(7)-tet-BMPR2(R899X) mice (model of PAH with universal expression of a mutated BMPR2 gene) with and without activation by LPS and in human lung tissue from HPAH with BMPR2 mutations and idiopathic PAH (IPAH). At baseline ETA and ETB receptors and endothelin converting enzyme (ECE) gene expression was reduced in BMPR2 mutant BMDM compared with controls. In control BMDM, LPS resulted in increased ppET-1 gene expression and ET-1 in culture media, whereas ETA and ETB receptor and ECE gene expression was decreased. These findings were more severe in BMPR2 mutant BMDM. Antagonism of the ETB receptor resulted in increased ET-1 in the media, suggesting that decreased ET-1 uptake by the ETB receptor contributes to the elevation. While ET-1 expression was demonstrated in lung macrophages from controls and IPAH and HPAH patients, ETA and ETB expression was decreased in the HPAH, but not IPAH, patients compared with controls. We conclude that reduced expression of macrophage ET-1 receptors in HPAH increases lung ET-1 and may contribute to the pathogenesis and maintenance of HPAH. This is the first description of protein expression that distinguishes HPAH from IPAH in patients.