Back to Search
Start Over
BMPR2 preserves mitochondrial function and DNA during reoxygenation to promote endothelial cell survival and reverse pulmonary hypertension.
- Source :
-
Cell metabolism [Cell Metab] 2015 Apr 07; Vol. 21 (4), pp. 596-608. - Publication Year :
- 2015
-
Abstract
- Mitochondrial dysfunction, inflammation, and mutant bone morphogenetic protein receptor 2 (BMPR2) are associated with pulmonary arterial hypertension (PAH), an incurable disease characterized by pulmonary arterial (PA) endothelial cell (EC) apoptosis, decreased microvessels, and occlusive vascular remodeling. We hypothesized that reduced BMPR2 induces PAEC mitochondrial dysfunction, promoting a pro-inflammatory or pro-apoptotic state. Mice with EC deletion of BMPR2 develop hypoxia-induced pulmonary hypertension that, in contrast to non-transgenic littermates, does not reverse upon reoxygenation and is associated with reduced PA microvessels and lung EC p53, PGC1α and TFAM, regulators of mitochondrial biogenesis, and mitochondrial DNA. Decreasing PAEC BMPR2 by siRNA during reoxygenation represses p53, PGC1α, NRF2, TFAM, mitochondrial membrane potential, and ATP and induces mitochondrial DNA deletion and apoptosis. Reducing PAEC BMPR2 in normoxia increases p53, PGC1α, TFAM, mitochondrial membrane potential, ATP production, and glycolysis, and induces mitochondrial fission and a pro-inflammatory state. These features are recapitulated in PAECs from PAH patients with mutant BMPR2.<br /> (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Subjects :
- Analysis of Variance
Animals
Blotting, Western
Bone Morphogenetic Protein Receptors, Type II metabolism
DNA metabolism
DNA Primers genetics
Flow Cytometry
Fluorescent Antibody Technique
HEK293 Cells
Humans
Hypertension, Pulmonary physiopathology
Membrane Potential, Mitochondrial physiology
Mice
Polymerase Chain Reaction
Pulmonary Artery cytology
RNA, Small Interfering genetics
Cell Survival physiology
Endothelial Cells physiology
Hypertension, Pulmonary metabolism
Mitochondria metabolism
Models, Biological
Pulmonary Artery physiology
Regeneration physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1932-7420
- Volume :
- 21
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Cell metabolism
- Publication Type :
- Academic Journal
- Accession number :
- 25863249
- Full Text :
- https://doi.org/10.1016/j.cmet.2015.03.010