Bone morphogenetic protein signalling in heritable versus idiopathic pulmonary hypertension
Bone morphogenetic protein signalling in heritable versus idiopathic pulmonary hypertension
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DOI：
10.1183/09031936.00183008
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发表时间：
2009-11-01
影响因子：
24.3
通讯作者：
Eddahibi, S.
中科院分区：
文献类型：
--
作者：
Dewachter, L.;Adnot, S.;Eddahibi, S.
为研究骨形态发生蛋白2型受体（BMPR-2）基因突变与肺动脉高压（PAH）的关系，检测了19例特发性PAH患者和9例BMPR-2基因突变的遗传性PAH患者肺组织和培养的肺动脉平滑肌细胞（PASMC）中BMP受体的表达。BMP 4处理的PASMCs的Smad和p38丝裂原活化蛋白激酶（MAPK）信号与有丝分裂和凋亡进行了评估。肺组织和PASMCs从遗传性PAH患者呈现BMPR-2表达下降和BMPR-1A和BMPR-1B表达的可变增加，而在特发性PAH患者的PASMCs中观察到不太重要的BMPR-2表达下降。在BMP 4存在下，可遗传的PAH PASMCs显示Smad 1/5/8磷酸化没有增加，这实际上激活了p38 MAPK通路。个体反应因突变而异。PAH患者的PASMCs在体外呈现增殖模式，在特发性PAH中可以被BMP 4抑制，但在遗传性PAH中不能。特发性PAH的PASMC和遗传性PAH的PASMC对BMP 4诱导的凋亡有抑制作用，大多数异质性BMPR-2突变与Smad信号缺陷相关，而p38 MAPK信号的激活弥补了Smad信号缺陷，导致PASMC增殖和凋亡缺陷。
Mutations in the gene encoding bone morphogenetic protein (BMP) receptor type 2 (BMPR-2) have been reported in pulmonary arterial hypertension (PAH), but their functional relevance remains incompletely understood.BMP receptor expression was evaluated in human lungs and in cultured pulmonary artery smooth muscle cells (PASMCs) isolated from 19 idiopathic PAH patients and nine heritable PAH patients with demonstrated BMPR-2 mutations. BMP4-treated PASMCs were assessed for Smad and p38 mitogen-activated protein kinase (MAPK) signalling associated with mitosis and apoptosis.Lung tissue and PASMCs from heritable PAH patients presented with decreased BMPR-2 expression and variable increases in BMPR-1A and BMPR-1B expression, while a less important decreased BMPR-2 expression was observed in PASMCs from idiopathic PAH patients. Heritable PAH PASMCs showed no increased phosphorylation of Smad1/5/8 in the presence of BMP4, which actually activated the p38MAPK pathway. Individual responses varied from one mutation to another. PASMCs from PAH patients presented with an in vitro proliferative pattern, which could be inhibited by BMP4 in idiopathic PAH but not in heritable PAH. PASMCs from idiopathic PAH and more so from heritable PAH presented an inhibition of BMP4-induced apoptosis.Most heterogeneous BMPR-2 mutations are associated with defective Smad signalling compensated for by an activation of p38MAPK signalling, accounting for PASMC proliferation and deficient apoptosis.