Abstract 13936: Increased Bone Morphogenetic Protein 10 in Pulmonary Hypertension

Abstract

Introduction: Pulmonary Hypertension (PH) is characterized by increased right atrial (RA) stretch and pressure. The major genetic predisposing risk factor for PH involves mutations in the 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 despite an elusive BMP10 release mechanism. Hypothesis: Increased RA wall stress in PH may be a trigger for BMP10 secretion. Methods: We first investigated BMP10 gene and protein expressions, as well as BMP activity, in RA tissue samples from control (N=5) and PH-patients (N=4). We also quantified BMP10, BMP9, IL-6 and active TGF-β plasma levels in controls (N=16) and PH-patients (N=48) by ELISA. We studied BMP10 and BMP9 activities, using a BMP-inducible reporter assay. Last, we established correlations between BMP10 activity and PH clinical parameters. Results: BMP10 mRNA, protein and activity (pSMAD1/5/8 and ID3) were increased in RA tissue of PH-patients compared to controls (Figure1 A-E). BMP10, BMP9 and IL-6 plasma levels were also augmented (Figure1 F-H); while TGF-β plasma levels, and BMP10 and BMP9 activities between PH-patients and controls were preserved. Finally, we divided the PH cohort on median BMP10-activity (0.33 AU). Higher BMP10 activity in PH-patients was associated with diminished RA compliance, reduced right ventricular function, lower stroke volume and elevated NT-proBNP (Figure1 I). Conclusions: Although BMP10 plasma levels were increased, BMP10 activity was preserved in PH-patients, probably because of high inflammatory cytokines, such as IL-6. High BMP10 activity was associated with increased RA pressure and worse disease severity in PH-patients.