Oxidative Injury is a Common Consequence of BMPR2 Mutations

PVRI Member Authors: Kirk B Lane, Eric Austin, Anna Hemnes, Dr. Josh Fessel, James West


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 the molecular etiology of the disease. The objective of this study was to determine the common molecular consequences across classes of BMPR2 mutation. Increased superoxide and peroxide production and alterations in genes associated with oxidative stress were a common consequence of stable transfection of the 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 two-fold increase in isofurans, suggesting increased reactive oxygen species (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 the 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 hereditary PAH patient lung confirmed oxidative stress specific to the vasculature. Increased oxidative stress, likely of mitochondrial origin, is a common consequence of BMPR2 mutation across mutation types in cell culture, mice and humans.

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Mitochondrial Function
Oxidative stress and Oxidants/Antioxidants and Free Radicals
Preclinical and Molecular Science


Kirk L. Lane, Megha Talati, Eric Austin, Anna R. Hemnes, Jennifer A. Johnson, Joshua P. Fessel, Tom Blackwell, Ray L. Mernaugh, Linda Robinson, Candice Fike, L. Jackson Roberts, II, James West

Published in:

Pulmonary Circulation Vol 1: No 1 cover image

March 2011

Pulmonary Circulation Vol 1: No 1

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