Oxidative injury is a common consequence of BMPR2 mutations

BACKGROUND: Hereditary pulmonary arterial hypertension(PAH) is usually caused by mutations in BMPR2. Mutations are found throughout the gene, and common molecular consequences of different types of mutation are not known. Knowledge of common molecular consequences would provide insight into molecular etiology of disease. The objective of this study was to determine common molecular consequences across classes of BMPR2 mutation. METHODS #ENTITYSTARTX00026; RESULTS: Increased superoxide and peroxide production, and alterations in genes associated with oxidative stress were a common consequence of stable transfection of vascular smooth muscle cells with three distinct classes of BMPR2 mutation, in the ligand binding domain, the kinase domain, and the cytoplasmic tail domain. Measurement of oxidized lipids in whole lung from transgenic mice expressing a mutation in the BMPR2 cytoplasmic tail showed a 50% increase in isoprostanes and a twofold increase in isofurans, suggesting increased ROS of mitochondrial origin. Immunohistochemistry on BMPR2 transgenic mouse lung showed that oxidative stress was vascular-specific. Electron microscopy showed decreased mitochondrial size and variability in pulmonary vessels from BMPR2 mutant mice. Measurement of oxidized lipids in urine from humans with BMPR2 mutations demonstrated increased ROS, regardless of disease status. Immunohistochemistry on HPAH patient lung confirmed oxidative stress specific to the vasculature. CONCLUSIONS: Increased oxidative stress, likely of mitochondrial origin, is a common consequence of BMPR2 mutation across mutation types in cell culture, mice, and humans.