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Published on: January 16, 2013
BMPR2 mutation alters the lung macrophage endothelin-1 cascade in a mouse model and patients with heritable pulmonary
M Talati1, J West, T R Blackwell
1Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 27232-2650, USA. Megha.Talati@vanderbilt.edu
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.
Insights
Reduced endothelin-1 (ET-1) receptor expression in macrophages of heritable pulmonary artery hypertension (HPAH) patients increases lung ET-1. This may drive HPAH development and progression, distinguishing it from idiopathic PAH.
Area of Science:
- Pulmonary Hypertension Research
- Endothelin System Signaling
- Macrophage Biology
Background:
- Macrophage-derived endothelin-1 (ET-1) is implicated in chronic lung diseases.
- The role of ET-1 from inflammatory cells in pulmonary artery hypertension (PAH), especially heritable PAH (HPAH) with BMPR2 mutations, remains unclear.
Purpose of the Study:
- To investigate the contribution of the ET-1 cascade from non-vascular sources, specifically macrophages, to PAH pathogenesis.
- To determine if reduced bone morphogenetic protein type 2 receptor (BMPR2) impacts ET-1 signaling in macrophages.
- To differentiate HPAH from idiopathic PAH (IPAH) based on macrophage ET-1 receptor expression.
Main Methods:
- Utilized a mouse model (ROSA26rtTAXTetO(7)-tet-BMPR2(R899X)) with mutated BMPR2 in bone marrow-derived macrophages (BMDM).
- Stimulated BMDM with lipopolysaccharide (LPS) and analyzed gene expression of ET-1, ET(A) receptors, ET(B) receptors, and endothelin-converting enzyme (ECE).
- Examined ET-1, ET(A), and ET(B) receptor expression in human lung tissue from HPAH, IPAH, and control patients.
Main Results:
- BMPR2 mutant BMDM showed reduced baseline ET(A)/ET(B) receptor and ECE gene expression.
- LPS stimulation increased ET-1 in control BMDM but decreased receptor/ECE expression; these effects were exacerbated in BMPR2 mutant BMDM.
- Reduced ET(A)/ET(B) receptor expression was observed in HPAH macrophages, unlike IPAH, correlating with increased lung ET-1.
Conclusions:
- Decreased macrophage ET-1 receptor expression in HPAH contributes to elevated lung ET-1 levels.
- This macrophage-mediated ET-1 dysregulation is a potential driver for HPAH pathogenesis and maintenance.
- Macrophage ET-1 receptor expression profiles can distinguish HPAH from IPAH.
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