BMPR2 preserves mitochondrial function and DNA during reoxygenation to promote endothelial cell survival and reverse pulmonary hypertension.
BMPR2 preserves mitochondrial function and DNA during reoxygenation to promote endothelial cell survival and reverse pulmonary hypertension.
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BMPR2在氧化过程中保留线粒体功能和DNA，以促进内皮细胞的存活和反向肺动脉高压。
DOI：
10.1016/j.cmet.2015.03.010
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发表时间：
2015-04-07
期刊：
影响因子：
29
通讯作者：
Rabinovitch M
中科院分区：
文献类型：
--
作者：
Diebold I;Hennigs JK;Miyagawa K;Li CG;Nickel NP;Kaschwich M;Cao A;Wang L;Reddy S;Chen PI;Nakahira K;Alcazar MA;Hopper RK;Ji L;Feldman BJ;Rabinovitch M
线粒体功能障碍、炎症和骨形态发生蛋白受体(BMPR)2突变与肺动脉高压(PAH)有关，PAH是一种以肺动脉内皮细胞(EC)凋亡、微血管减少和闭塞性血管重构为特征的难治性疾病。我们假设，BMPR2的减少会导致PAEC线粒体功能障碍，促进促炎或促凋亡状态。BMPR2EC缺失的小鼠会出现缺氧性肺动脉高压，与非转基因小鼠相比，这种情况在复氧后不会逆转，并与PA微血管和肺EC P53、PGC1DNA和TFAM减少有关，这些都是线粒体生物发生和线粒体α的调节因子。在复氧过程中，通过siRNA降低PAEC BMPR2的表达，可抑制P53、PgC1DNA、NRF2、TFAM、线粒体膜电位和α，并诱导线粒体DNA缺失和细胞凋亡。在常氧下降低PAECBMPR2可增加P53、PgC1ATP、TFAM、线粒体膜电位、α的产生和糖酵解，诱导线粒体分裂和促炎状态。这些特征在带有突变BMPR2的PAH患者的PAEC中得到了概括。
Mitochondrial dysfunction, inflammation and mutant bone morphogenetic protein receptor (BMPR)2 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, induces mitochondrial fission, and a pro-inflammatory state. These features are recapitulated in PAEC from PAH patients with mutant BMPR2.
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影响因子：
3.7
作者：
Julian MW;Shao G;Vangundy ZC;Papenfuss TL;Crouser ED
通讯作者：
Crouser ED
影响因子：
6
作者：
Fijalkowska, Iwona;Xu, Weiling;Tuder, Rubin M.
通讯作者：
Tuder, Rubin M.
影响因子：
15.9
作者：
Hansmann, Georg;de Jesus Perez, Vinicio A.;Rabinovitch, Marlene
通讯作者：
Rabinovitch, Marlene
DOI：
10.1083/jcb.201010051
发表时间：
2011-05-30
期刊：
The Journal of cell biology
影响因子：
--
作者：
Heo KS;Lee H;Nigro P;Thomas T;Le NT;Chang E;McClain C;Reinhart-King CA;King MR;Berk BC;Fujiwara K;Woo CH;Abe J
通讯作者：
Abe J
影响因子：
20.1
作者：
Diebold, Isabel;Djordjevic, Talija;Goerlach, Agnes
通讯作者：
Goerlach, Agnes