Selective enhancement of endothelial BMPR-II with BMP9 reverses pulmonary arterial hypertension.
Selective enhancement of endothelial BMPR-II with BMP9 reverses pulmonary arterial hypertension.
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DOI：
10.1038/nm.3877
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发表时间：
2015-07
期刊：
影响因子：
82.9
通讯作者：
Morrell, Nicholas W.
中科院分区：
文献类型：
--
作者：
Long, Lu;Ormiston, Mark L.;Yang, Xudong;Southwood, Mark;Graef, Stefan;Machado, Rajiv D.;Mueller, Matthias;Kinzel, Bernd;Yung, Lai Ming;Wilkinson, Janine M.;Moore, Stephen D.;Drake, Kylie M.;Aldred, Micheala A.;Yu, Paul B.;Upton, Paul D.;Morrell, Nicholas W.
遗传学证据表明，内皮细胞中骨形态发生蛋白II型受体（BMPR-II）信号转导的丢失是肺动脉高压（PAH）的起始因素。然而，使用BMP配体选择性靶向该信号传导途径尚未被探索为治疗策略。我们确定BMP9是预防肺动脉内皮细胞和血液生长内皮细胞凋亡和增强单层完整性的首选配体，这些内皮细胞来自携带BMPR-II突变的PAH受试者。在体内，我们报告了自发产生PAH的小鼠模型轴承杂合子敲入的人BMPR-II突变，R899X。施用BMP 9逆转了Bmpr2 +/R899X小鼠中建立的PAH，以及在响应于野百合碱或VEGF受体抑制与慢性缺氧组合而发展的疾病模型中。这些结果表明，直接增强内皮BMP信号传导作为PAH的一种新的治疗策略的前景。
Genetic evidence implicates the loss of bone morphogenetic protein type II receptor (BMPR-II) signaling in the endothelium as an initiating factor in pulmonary arterial hypertension (PAH). However, selective targeting of this signaling pathway using BMP ligands has not yet been explored as a therapeutic strategy. We identified BMP9 as the preferred ligand for preventing apoptosis and enhancing monolayer integrity in both pulmonary arterial endothelial cells and blood outgrowth endothelial cells from subjects with PAH bearing mutations in BMPR-II. In vivo, we report the spontaneous generation of PAH in a mouse model bearing a heterozygous knock-in of a human BMPR-II mutation, R899X. Administration of BMP9 reversed established PAH in Bmpr2+/R899X mice, as well as in models of disease developed in response to either monocrotaline or VEGF receptor inhibition combined with chronic hypoxia. These results demonstrate the promise of direct enhancement of endothelial BMP signaling as a novel therapeutic strategy for PAH.
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影响因子：
37.8
作者：
Hong KH;Lee YJ;Lee E;Park SO;Han C;Beppu H;Li E;Raizada MK;Bloch KD;Oh SP
通讯作者：
Oh SP
DOI：
10.1165/rcmb.2002-0085oc
发表时间：
2003-05-01
影响因子：
6.4
作者：
Harrington, EO;Brunelle, JL;Rounds, S
通讯作者：
Rounds, S
影响因子：
2.7
作者：
Beppu, H;Kawabata, M;Miyazono, K
通讯作者：
Miyazono, K
影响因子：
5.1
作者：
Kang, Q;Sun, MH;He, TC
通讯作者：
He, TC
影响因子：
3.7
作者：
Frump AL;Lowery JW;Hamid R;Austin ED;de Caestecker M
通讯作者：
de Caestecker M