Altered expression and signal transduction of endothelin-1 receptors in heritable and idiopathic pulmonary arterial hypertension.
Altered expression and signal transduction of endothelin-1 receptors in heritable and idiopathic pulmonary arterial hypertension.
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DOI：
10.1002/jcp.24132
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发表时间：
2013-02
影响因子：
5.6
通讯作者：
Polgar, Peter
中科院分区：
文献类型：
--
作者：
Yu, Jun;Taylor, Linda;Wilson, Jamie;Comhair, Suzy;Erzurum, Serpil;Polgar, Peter
人肺动脉平滑肌细胞（PASMC）分离自弹性肺动脉解剖与肺动脉高压（PAH）和非个人的肺。反映PAH受试者细胞中平滑肌收缩增加，相对于正常供体对照细胞，所有PAH PASMC群体中响应内皮素-1（ET-1）的Ca 2+内流增加。在遗传性和特发性PAH衍生的PASMC中，ETA受体mRNA水平保持不变，而ETB受体mRNA水平降低。与ETB受体数量相比，所有PASMC群体表达相当高的ETA。在骨形态发生蛋白受体II型（BMPR 2）突变PAH中，ETA和ETB受体数量均减少。ETB受体的数量特别减少。正常和BMPR 2缺失的PASMC的磷酸化抗体阵列分析表明，ERK和Akt激活是最突出的，并且主要通过正常PASMC中的ETB受体发生，但主要通过BMPR 2 PAH受试者的PASMC中的ETA受体发生。此外，在PAH细胞中，总的相对ET-1信号反应显着降低。BMPR 2 PASMC的Western分析重复了阵列结果，而iPAH受试者的PASMC显示变异性，大多数样本继续通过ETB发出信号。总之，这些结果表明，通常两种受体在PAH中减少，特别是ETB，并且通过蛋白激酶的ETB信号传导在BMPR 2 PASMC中显著减少，而在IPAH中继续。重要的是，数据表明，在PAH患者中应用ET-1受体拮抗剂治疗时必须谨慎。
Human pulmonary arterial smooth muscle cells (PASMC) were isolated from elastic pulmonary arteries dissected from lungs of individuals with and without pulmonary arterial hypertension (PAH). Reflecting increased smooth muscle constriction in cells from PAH subject, Ca2+ influx in response to endothelin-1 (ET-1) increased in all the PAH PASMC populations relative to the normal donor control cells. The ETA receptor mRNA levels remained unchanged, whereas the ETB receptor mRNA levels decreased in both heritable and idiopathic PAH derived PASMC. All the PASMC populations expressed considerably higher ETA compared to ETB receptor number. Both ETA and ETB receptor numbers were reduced in bone morphogenetic protein receptor type II (BMPR2) mutation PAH. ETB receptors showed a particular reduction in number. Phospho-antibody array analysis of normal and BMPR2 deletion PASMC illustrated ERK and Akt activation to be the most prominent and to be taking place principally through ETB receptors in normal PASMC, but primarily through ETA receptors in PASMC from BMPR2 PAH subjects. Additionally in the PAH cells the total relative ET-1 signal response was markedly reduced. Western analysis from the BMPR2 PASMC duplicated the array results whereas PASMC from iPAH subjects showed variability with most samples continuing to signal through ETB. In sum, these results indicate that generally both receptors are reduced in PAH particularly ETB, and that ETB signaling through protein kinases becomes markedly reduced in BMPR2 PASMC while it continues in IPAH. Importantly the data suggest that caution must be taken when applying ET-1 receptor antagonist therapy to PAH patients.
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影响因子：
158.5
作者：
GIAID, A;YANAGISAWA, M;STEWART, DJ
通讯作者：
STEWART, DJ
DOI：
10.1164/rccm.201003-0491oc
发表时间：
2010-11-01
影响因子：
24.7
作者：
Aldred, Micheala A.;Comhair, Suzy A.;Coldren, Christopher D.
通讯作者：
Coldren, Christopher D.
影响因子：
7.3
作者：
de Lagausie, P;de Buys-Roessingh, A;Berrebi, D
通讯作者：
Berrebi, D
影响因子：
24
作者：
Humbert, M;Morrell, NW;Rabinovitch, M
通讯作者：
Rabinovitch, M
影响因子：
4.3
作者：
Masaki, T;Ninomiya, H;Okamoto, Y
通讯作者：
Okamoto, Y