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Oxidative injury is a common consequence of BMPR2 mutations
Kirk L Lane1, Megha Talati1, Eric Austin2, Anna R Hemnes1, Jennifer A Johnson1, Joshua P Fessel1, Tom Blackwell1, Ray L Mernaugh3, Linda Robinson1, Candice Fike4, L Jackson Roberts II5, James West1
1 Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
2 Department of Genetics and Biochemistry, Vanderbilt University Medical Center, Nashville, Tennessee, USA
3 Department of Biochemistry, Vanderbilt University Medical Center, Nashville, Tennessee, USA
4 Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
5 Department of Medicine and Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
Correspondence Address:
James West
Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center, 1161 21st Avenue South, Suite T-1218 (MCN), Nashville, Tennessee 37232-2650
USA
DOI: 10.4103/2045-8932.78107 PMID: 21904662
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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. |
