BMPR2 preserves mitochondrial function and DNA during reoxygenation to promote endothelial cell survival and reverse pulmonary hypertension
Standard
BMPR2 preserves mitochondrial function and DNA during reoxygenation to promote endothelial cell survival and reverse pulmonary hypertension. / Diebold, Isabel; Hennigs, Jan K; Miyagawa, Kazuya; Li, Caiyun G; Nickel, Nils P; Kaschwich, Mark; Cao, Aiqin; Wang, Lingli; Reddy, Sushma; Chen, Pin-I; Nakahira, Kiichi; Alcazar, Miguel A Alejandre; Hopper, Rachel K; Ji, Lijuan; Feldman, Brian J; Rabinovitch, Marlene.
in: CELL METAB, Jahrgang 21, Nr. 4, 07.04.2015, S. 596-608.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
Harvard
APA
Vancouver
Bibtex
}
RIS
TY - JOUR
T1 - BMPR2 preserves mitochondrial function and DNA during reoxygenation to promote endothelial cell survival and reverse pulmonary hypertension
AU - Diebold, Isabel
AU - Hennigs, Jan K
AU - Miyagawa, Kazuya
AU - Li, Caiyun G
AU - Nickel, Nils P
AU - Kaschwich, Mark
AU - Cao, Aiqin
AU - Wang, Lingli
AU - Reddy, Sushma
AU - Chen, Pin-I
AU - Nakahira, Kiichi
AU - Alcazar, Miguel A Alejandre
AU - Hopper, Rachel K
AU - Ji, Lijuan
AU - Feldman, Brian J
AU - Rabinovitch, Marlene
N1 - Copyright © 2015 Elsevier Inc. All rights reserved.
PY - 2015/4/7
Y1 - 2015/4/7
N2 - 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.
AB - 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.
U2 - 10.1016/j.cmet.2015.03.010
DO - 10.1016/j.cmet.2015.03.010
M3 - SCORING: Journal article
C2 - 25863249
VL - 21
SP - 596
EP - 608
JO - CELL METAB
JF - CELL METAB
SN - 1550-4131
IS - 4
ER -