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• W2087506384 abstract "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 ET A and ET B 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 ET A and ET B receptor and ECE gene expression was decreased. These findings were more severe in BMPR2 mutant BMDM. Antagonism of the ET B receptor resulted in increased ET-1 in the media, suggesting that decreased ET-1 uptake by the ET B receptor contributes to the elevation. While ET-1 expression was demonstrated in lung macrophages from controls and IPAH and HPAH patients, ET A and ET B 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." @default.
• W2087506384 created "2016-06-24" @default.
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• W2087506384 date "2010-09-01" @default.
• W2087506384 modified "2023-10-14" @default.
• W2087506384 title "BMPR2 mutation alters the lung macrophage endothelin-1 cascade in a mouse model and patients with heritable pulmonary artery hypertension" @default.
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• W2087506384 doi "https://doi.org/10.1152/ajplung.00295.2009" @default.
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