Hidekazu Maruyama1, Céline Dewachter1, Asmae Belhaj2, Benoit Rondelet2, Satoshi Sakai3, Myriam Remmelink4, Jean-Luc Vachiery5, Robert Naeije1, Laurence Dewachter6. 1. Laboratory of Physiology and Physiopathology, Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium. 2. Laboratory of Physiology and Physiopathology, Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium; Department of Thoracic Surgery, Erasmus University Hospital, Brussels, Belgium; Department of Cardio-Vascular and Thoracic Surgery and Lung Transplantation, Mont-Godinne University Hospital, Dinant, Belgium. 3. Cardiovascular Division, Department of Internal Medicine, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan and the Departments of. 4. Anatomopathology. 5. Cardiology, Erasmus University Hospital, Brussels, Belgium. 6. Laboratory of Physiology and Physiopathology, Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium. Electronic address: ldewacht@ulb.ac.be.
Abstract
BACKGROUND: Endothelin receptor antagonists improve pulmonary arterial hypertension (PAH). Mutations in the bone morphogenetic protein (BMP) type 2 receptor (BMPR2) predispose to PAH. Here, we sought to determine whether there might exist interactions between these 2 signaling pathways and their effect on the acquisition of the altered phenotype of pulmonary artery smooth muscle cells (PA-SMCs) observed in PAH. METHODS: Expression of BMPR2, of the BMP agonist BMP4, and of the BMP antagonists gremlin1 and gremlin2 was evaluated in lungs and in PA-SMCs from 6 PAH patients and 14 controls treated with endothelin-1. Endothelin-1 pre-treated PA-SMCs were assessed for proliferation, apoptosis, and downstream signaling activation of Smad1/5/8 and p38 mitogen-activated protein kinase (p38(MAPK)) after BMP2 treatment. RESULTS: In PA-SMCs from PAH patients, expression of BMPR2 and BMP4 decreased, whereas expression of gremlin1 and gremlin2 increased compared with controls. Treatment of control PA-SMCs with endothelin-1 induced a dose-dependent increase in gremlin1 and gremlin2, whereas BMPR2 and BMP4 expression decreased, reaching similar levels as those observed in PAH cells. In control PA-SMCs, endothelin-1 pre-treatment reduced inhibitor of DNA binding 1 (Id1) expression and Smad1/5/8 activation induced by BMP2, whereas it enhanced p38(MAPK) activation. Moreover, BMP2 decreased serum-induced proliferation and increased the pro-apoptotic Bax/Bcl-2 ratio. These effects were attenuated by endothelin-1 pre-treatment. Endothelin-1 did not alter BMPR2 signaling in PA-SMCs from PAH patients. CONCLUSIONS: Endothelin-1 downregulates canonical BMPR2 signaling. This is related to decreased BMPR2 and increased anti-BMP gremlin expression associated with increased activation of p38(MAPK) and results in PA-SMC proliferation.
BACKGROUND: Endothelin receptor antagonists improve pulmonary arterial hypertension (PAH). Mutations in the bone morphogenetic protein (BMP) type 2 receptor (BMPR2) predispose to PAH. Here, we sought to determine whether there might exist interactions between these 2 signaling pathways and their effect on the acquisition of the altered phenotype of pulmonary artery smooth muscle cells (PA-SMCs) observed in PAH. METHODS: Expression of BMPR2, of the BMP agonist BMP4, and of the BMP antagonists gremlin1 and gremlin2 was evaluated in lungs and in PA-SMCs from 6 PAH patients and 14 controls treated with endothelin-1. Endothelin-1 pre-treated PA-SMCs were assessed for proliferation, apoptosis, and downstream signaling activation of Smad1/5/8 and p38 mitogen-activated protein kinase (p38(MAPK)) after BMP2 treatment. RESULTS: In PA-SMCs from PAH patients, expression of BMPR2 and BMP4 decreased, whereas expression of gremlin1 and gremlin2 increased compared with controls. Treatment of control PA-SMCs with endothelin-1 induced a dose-dependent increase in gremlin1 and gremlin2, whereas BMPR2 and BMP4 expression decreased, reaching similar levels as those observed in PAH cells. In control PA-SMCs, endothelin-1 pre-treatment reduced inhibitor of DNA binding 1 (Id1) expression and Smad1/5/8 activation induced by BMP2, whereas it enhanced p38(MAPK) activation. Moreover, BMP2 decreased serum-induced proliferation and increased the pro-apoptotic Bax/Bcl-2 ratio. These effects were attenuated by endothelin-1 pre-treatment. Endothelin-1 did not alter BMPR2 signaling in PA-SMCs from PAH patients. CONCLUSIONS:Endothelin-1 downregulates canonical BMPR2 signaling. This is related to decreased BMPR2 and increased anti-BMPgremlin expression associated with increased activation of p38(MAPK) and results in PA-SMC proliferation.
Authors: Jasmin Wellbrock; Lars Harbaum; Hauke Stamm; Jan K Hennigs; Björn Schulz; Hans Klose; Carsten Bokemeyer; Walter Fiedler; Nicole Lüneburg Journal: Lung Date: 2015-04-30 Impact factor: 2.584
Authors: Sachindra R Joshi; Jun Liu; Troy Bloom; Elif Karaca Atabay; Tzu-Hsing Kuo; Michael Lee; Elitza Belcheva; Matthew Spaits; Rosa Grenha; Michelle C Maguire; Jeffrey L Frost; Kathryn Wang; Steven D Briscoe; Mark J Alexander; Brantley R Herrin; Roselyne Castonguay; R Scott Pearsall; Patrick Andre; Paul B Yu; Ravindra Kumar; Gang Li Journal: Sci Rep Date: 2022-05-12 Impact factor: 4.996