Background: Pulmonary hypertension (PH) is characterized by increased right atrial (RA) stretch and pressure. The major genetic predisposing risk factor for PH involves mutations in bone morphogenetic protein (BMP) receptor 2 (BMPR2), for which BMP9 and BMP10 are ligands. Although BMP9 is mostly produced by hepatocytes, BMP10 is predominantly produced by adult RA cardiomyocytes. Therefore, its role is of interest in PH. However, the mechanism leading to BMP10 release remains elusive.
Methods: We analysed BMP10 and BMP9 plasma levels in PH patients using enzyme-linked immunosorbent assay [n = 22 idiopathic pulmonary arterial hypertension (iPAH), n = 14 hereditary PAH (hPAH) and n = 11 chronic thromboembolic PH (CTEPH)] and n = 16 controls. To determine BMP10 and BMP9 activity, we exposed endothelial cells to 10% serum. BMP activity was analyzed as the read out of a BRE-luciferase reporter assay. Serum was incubated with trap antibodies: anti-BMP9 to inhibit BMP9 ligand and ALK1-Fc to inhibit both BMP9 and BMP10 ligands. Consequently, we deducted BMP9 and BMP10 transcriptional activity from the difference versus baseline and BMP9 activity.
Results: Plasma BMP10 levels were increased in PH-patients: 16.5 (9.5–69.7) pg/mL in iPAH, 17.1 (1.4–113.4) pg/mL in hPAH and 37.8 (10.7–87.1) pg/mL in CTEPH, versus 6.1 (0–8.7) pg/mL in control. We did not detect differences in BMP9 levels. In addition, BMP10 and BMP9 transcriptional activity was unaltered. Next, we divided the PH-cohort on median BMP10 activity (0.33 a.u.). Higher transcriptional BMP10 activity in PH patients was associated with increased RA volume and pressure and reduced RA compliance. Furthermore, higher BMP10 transcriptional activity was associated with worse disease status, shown by worse right ventricular function, reduced stroke volume and elevated N-terminal pro-brain natriuretic peptide levels.
Conclusions: Although BMP10 circulating levels were increased, transcriptional BMP10 activity was preserved in PH patients. No differences were observed in BMP9 levels or activity. High BMP10 activity was associated with increased RA pressure and worse disease severity in PH patients.
A. Llucià-Valldeperas*, J. van Wezenbeek*, J. A. Groeneveldt, Department of Pulmonary Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands G. Sanchez-Duffhues, Cell and Chemical Biology, Leiden UMC, Leiden, Netherlands R. Smal, X. Pan, A. Vonk Noordegraaf, H. J. Bogaard, Department of Pulmonary Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands M. J. Goumans, Cell and Chemical Biology, Leiden UMC, Leiden, The Netherlands F. S. de Man, Department of Pulmonary Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands