PT  - JOURNAL ARTICLE
AU  - Hidekazu Maruyama
AU  - Celine Dewachter
AU  - Asmae Belhaj
AU  - Benoit Rondelet
AU  - Myriam Remmelink
AU  - Jean-Luc Vachiery
AU  - Robert Naeije
AU  - Laurence Dewachter
TI  - Endothelin-1 downregulates BMP signaling in pulmonary artery smooth muscle cells
DP  - 2012 Sep 01
TA  - European Respiratory Journal
PG  - P954
VI  - 40
IP  - Suppl 56
4099  - http://erj.ersjournals.com/content/40/Suppl_56/P954.short
4100  - http://erj.ersjournals.com/content/40/Suppl_56/P954.full
SO  - Eur Respir J2012 Sep 01; 40
AB  - Increased endothelin-1 (ET-1) and decreased bone morphogenetic protein (BMP) receptor type 2 (BMPR2) signaling pathways have been shown to be implicated in the pathogenesis of pulmonary arterial hypertension (PAH). However, little is known about the interaction between these two signaling pathways and its implication in the generation of altered pulmonary artery smooth muscle cell (PA-SMC) phenotype in PAH.We further explored BMP signaling in PA-SMCs isolated from PAH patients and the effects of ET-1 treatment on the expressions of BMPR2, BMP agonists (BMP4) and antagonists (gremlin-1, gremlin-2 and noggin) in PA-SMCs.We therefore quantified, by RTQ-PCR, the gene expressions of BMPR2, BMP agonists and antagonists in primary cultures of PA-SMCs isolated from PAH patients (n=4) and controls (n=9). We evaluated the effects of increasing concentrations of ET-1 (10-6M and 10-7M) on the expression of these BMP signaling members in control PA-SMCs.PA-SMCs isolated from PAH patients presented with decreased BMPR2 gene expression, while gene expressions of gremlin-1, gremlin-2 and noggin increased in PA-SMCs isolated from PAH patients compared to controls. BMP4 gene expression increased in PA-SMCs isolated from PAH patients. Stimulation of control PA-SMCs with ET-1 induced an increase in mRNA encoding BMP antagonists (gremlin-1, gremlin-2 and noggin), while BMPR2 gene expression decreased dose-dependently. However, in ET-1-treated PA-SMCs, BMP4 expression did not change. After ET-1 treatment, levels of BMPR2 and BMP antagonists were similar as those observed in PA-SMCs isolated from PAH patients.Endothelium-derived ET-1 seems to contribute to altered BMPR2 signaling observed in PAH patients.