Endothelin-Bone morphogenetic protein type 2 receptor interaction induces pulmonary artery smooth muscle cell hyperplasia in pulmonary arterial hypertension
Endothelin-Bone morphogenetic protein type 2 receptor interaction induces pulmonary artery smooth muscle cell hyperplasia in pulmonary arterial hypertension
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DOI：
10.1016/j.healun.2014.09.011
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发表时间：
2015-03-01
影响因子：
8.9
通讯作者：
Dewachter, Laurence
中科院分区：
文献类型：
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作者：
Maruyama, Hidekazu;Dewachter, Celine;Dewachter, Laurence
背景：内皮素受体拮抗剂可改善肺动脉高压。骨形态发生蛋白（BMP）2型受体（BMPR 2）的突变易患PAR。在这里，我们试图确定这两种信号通路之间是否存在相互作用，以及它们对PAR中观察到的肺动脉平滑肌细胞（PA-SMCs）表型改变的获得的影响。BMPR 2、BMP激动剂BMP 4的表达，和BMP拮抗剂gremlin 1和gremlin 2在肺和PA-SMCs中进行了评价，这些肺和PA-SMCs来自6名PAR患者和14名对照者，这些患者接受了内皮素-1预处理，结果：与对照组相比，PAR患者肺动脉平滑肌细胞中BMPR 2和BMP 4表达降低，gremlin 1和gremlin 2表达升高，Smad 1/5/8和p38丝裂原活化蛋白激酶（p38（MAPK））下游信号通路活化程度降低。用内皮素-1处理对照PA-SMC诱导gremlin 1和gremlin 2的剂量依赖性增加，而BMPR 2和BMP 4表达降低，达到与PAR细胞中观察到的相似水平。在对照PA-SMCs中，内皮素-1预处理降低DNA结合抑制因子1（Id 1）表达和由BMP 2诱导的Smad 1/5/8活化，而增强p38（MAPK）活化。此外，BMP 2降低血清诱导的增殖，并增加促凋亡Bax/Bcl-2的比例。内皮素-1预处理可减弱这些作用。结论：内皮素-1下调了PAR患者PA-SMCs中典型的BMPR 2信号。这与BMPR 2减少和抗BMP gremlin表达增加有关，与p38（MAPK）激活增加相关，并导致PA-SMC增殖。(C)2015年国际心肺移植学会。All rights reserved.
BACKGROUND: Endothelin receptor antagonists improve pulmonary arterial hypertension (PAR). Mutations in the bone morphogenetic protein (BMP) type 2 receptor (BMPR2) predispose to PAR. Here, we sought to determine whether there might exist interactions between these 2 signaling pathways and their effect on the acquisition of the altered phenotype of pulmonary artery smooth muscle cells (PA-SMCs) observed in PAR.METHODS: Expression of BMPR2, of the BMP agonist BMP4, and of the BMP antagonists gremlin1 and gremlin2 was evaluated in lungs and in PA-SMCs from 6 PAR patients and 14 controls treated with endothelin-1 Endothelin-1 pre-treated PA-SMCs were assessed for proliferation, apoptosis, and downstream signaling activation of Smad1/5/8 and p38 mitogen-activated protein kinase (p38(MAPK)) after BMP2 treatment.RESULTS: In PA-SMCs from PAR patients, expression of BMPR2 and BMP4 decreased, whereas expression of gremlin1 and gremlin2 increased compared with controls. Treatment of control PA-SMCs with endothelin-1 induced a dose-dependent increase in gremlin1 and gremlin2, whereas BMPR2 and BMP4 expression decreased, reaching similar levels as those observed in PAR cells. In control PA-SMCs, endothelin-1 pre-treatment reduced inhibitor of DNA binding 1 (Id1) expression and Smad1/5/8 activation induced by BMP2, whereas it enhanced p38(MAPK) activation. Moreover, BMP2 decreased serum-induced proliferation and increased the pro-apoptotic Bax/Bcl-2 ratio. These effects were attenuated by endothelin-1 pre-treatment. Endothelin-1 did not alter BMPR2 signaling in PA-SMCs from PAR patients.CONCLUSIONS: Endothelin-1 downregulates canonical BMPR2 signaling. This is related to decreased BMPR2 and increased anti-BMP gremlin expression associated with increased activation of p38(MAPK) and results in PA-SMC proliferation. (C) 2015 International Society for Heart and Lung Transplantation. All rights reserved.