Dysregulated bone morphogenetic protein signaling in monocrotaline-induced pulmonary arterial hypertension
Dysregulated bone morphogenetic protein signaling in monocrotaline-induced pulmonary arterial hypertension
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DOI：
10.1161/atvbaha.107.141200
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发表时间：
2007-05-01
影响因子：
8.7
通讯作者：
Eickelberg, Oliver
中科院分区：
文献类型：
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作者：
Morty, Rory E.;Nejman, Bozena;Eickelberg, Oliver
背景-编码II型骨形态发生蛋白（BMP）受体的bmpr 2基因突变已在肺动脉高压（PAH）患者中发现，提示PAH中存在BMP信号传导。本研究的目的是评估BMP信号传导及其生理效应在野百合碱（MCT）模型PAH.Methods和结果-BMP受体Ib和II，和Smads 4，5，6和8的表达，下调在肺，但不是肾脏的MCT治疗的大鼠。Smad 1磷酸化和BMP/Smad靶基因id 1和id 3的表达也减少，尽管ERK 1/2和p38 MAPK磷酸化未受影响。MCT处理大鼠肺动脉平滑肌细胞（PASMCs）中BMP受体和Smad表达、Smad 1磷酸化和id 1启动子的BMP/Smad反应元件的诱导减少。由于受损的BMP/Smad信号，PASMCs从MCT处理的大鼠是抗凋亡诱导的BMP-4和BMP-7，也是抗BMP-4拮抗增殖诱导的血小板源性生长因子。结论- BMP信号和BMP调节的生理现象在MCT处理的大鼠扰乱，贷款固体支持BMP信号在人类PAH的发病机制中的作用。
Background - Mutations in the bmpr2 gene, encoding the type II bone morphogenetic protein (BMP) receptor, have been identified in patients with pulmonary arterial hypertension (PAH), implicating BMP signaling in PAH. The aim of this study was to assess BMP signaling and its physiological effects in a monocrotaline (MCT) model of PAH.Methods and Results - Expression of BMP receptors Ib and II, and Smads 4, 5, 6, and 8, was downregulated in lungs but not kidneys of MCT-treated rats. Smad1 phosphorylation and expression of BMP/Smad target genes id1 and id3 was also reduced, although ERK1/2 and p38MAPK phosphorylation remained unaffected. BMP receptor and Smad expression, Smad1 phosphorylation, and induction of the BMP/Smad-responsive element of the id1 promoter were reduced in pulmonary artery smooth muscle cells (PASMCs) from MCT-treated rats. As a consequence of impaired BMP/Smad signaling, PASMCs from MCT-treated rats were resistant to apoptosis induced by BMP-4 and BMP-7, and were also resistant to BMP-4 antagonism of proliferation induced by platelet-derived growth factor.Conclusion - BMP signaling and BMP-regulated physiological phenomena are perturbed in MCT-treated rats, lending solid support to the proposed roles for BMP signaling in the pathogenesis of human PAH.