[PDF][PDF] BMPR2 preserves mitochondrial function and DNA during reoxygenation to promote endothelial cell survival and reverse pulmonary hypertension

I Diebold, JK Hennigs, K Miyagawa, CG Li, NP Nickel… - Cell metabolism, 2015 - cell.com
I Diebold, JK Hennigs, K Miyagawa, CG Li, NP Nickel, M Kaschwich, A Cao, L Wang…
Cell metabolism, 2015cell.com
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 …
Summary
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.
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