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首页> 外文期刊>Cell metabolism >BMPR2 Preserves Mitochondrial Function and DNA during Reoxygenation to Promote Endothelial Cell Survival and Reverse Pulmonary Hypertension
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BMPR2 Preserves Mitochondrial Function and DNA during Reoxygenation to Promote Endothelial Cell Survival and Reverse Pulmonary Hypertension

机译：BMPR2在复氧过程中保留线粒体功能和DNA，以促进内皮细胞存活和逆转肺动脉高压。

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摘要

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, incontrast tonon-transgenic littermates, does not reverse upon reoxygenation and is associated with reduced PA microvessels and lung EC p53, PGC1 alpha and TFAM, regulators of mitochondrial biogenesis, and mitochondrial DNA. Decreasing PAEC BMPR2 by siRNA during reoxygenation represses p53, PGC1 alpha, NRF2, TFAM, mitochondrial membrane potential, and ATP and induces mitochondrial DNA deletion and apoptosis. Reducing PAEC BMPR2 in normoxia increases p53, PGC1 alpha, 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.
机译：线粒体功能障碍，炎症和突变的骨形态发生蛋白受体2（BMPR2）与肺动脉高压（PAH）相关，后者是一种以肺动脉（PA）内皮细胞（EC）凋亡，微血管减少和闭塞性血管重塑为特征的无法治愈的疾病。我们假设降低的BMPR2诱导PAEC线粒体功能障碍，促进促炎或促凋亡状态。 EC缺失BMPR2的小鼠发展为低氧诱导的肺动脉高压，与非转基因同窝仔动物相反，复氧后不会逆转，并且与PA微血管和肺EC p53，PGC1 alpha和TFAM减少，线粒体生物发生调节剂和线粒体DNA相关。 siRNA在复氧过程中降低PAEC BMPR2会抑制p53，PGC1 alpha，NRF2，TFAM，线粒体膜电位和ATP，并诱导线粒体DNA缺失和凋亡。减少常氧中的PAEC BMPR2会增加p53，PGC1 alpha，TFAM，线粒体膜电位，ATP产生和糖酵解，并诱导线粒体裂变和促炎状态。这些特征在具有突变的BMPR2的PAH患者的PAEC中得以概括。

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