Idiopathic and heritable PAH perturb common molecular pathways, correlated with increased MSX1 expression.
Idiopathic and heritable PAH perturb common molecular pathways, correlated with increased MSX1 expression.
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DOI：
10.4103/2045-8932.87308
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发表时间：
2011-07
影响因子：
2.6
通讯作者：
West J
中科院分区：
文献类型：
--
作者：
Austin ED;Menon S;Hemnes AR;Robinson LR;Talati M;Fox KL;Cogan JD;Hamid R;Hedges LK;Robbins I;Lane K;Newman JH;Loyd JE;West J
大多数肺动脉高压（PAH）与BMPR 2突变无关，特发性PAH的主要风险因素尚不清楚。本研究的目的是鉴定IPAH的基因表达特征。为了实现这一目标，我们使用Affyssin阵列探测86名患者样本的表达水平，包括22名健康对照，20名IPAH患者，20名遗传性PAH患者（HPAH）和24名尚未受影响的BMPR 2突变携带者（UMC）。培养患者细胞消除了药物作用和炎症的特征，这些特征使得对新鲜分离的淋巴细胞结果的解释成为问题。我们发现IPAH患者的基因表达特征与HPAH患者或单个不同的组聚集在一起。没有一组基因在IPAH中发生了变化，而在HPAH中也没有发生变化。HPAH、IPAH和UMC在代谢、肌动蛋白动力学、粘附、细胞因子、代谢、通道、分化和转录因子方面有共同的变化。共同IPAH和HPAH，但不是UMC的上调囊泡运输，氧化/亚硝化应激，和细胞周期基因。已知调节BMP信号的转录因子MSX 1是IPAH患者中上调最多的基因（4×）。这些结果表明，IPAH病例有一个共同的分子起源，这是密切相关的，但不同于，HPAH。HPAH和IPAH共享大多数改变的信号通路，这表明针对HPAH分子病因的治疗也将对IPAH有效。
The majority of pulmonary arterial hypertension (PAH) is not associated with BMPR2 mutation, and major risk factors for idiopathic PAH are not known. The objective of this study was to identify a gene expression signature for IPAH. To accomplish this, we used Affymetrix arrays to probe expression levels in 86 patient samples, including 22 healthy controls, 20 IPAH patients, 20 heritable PAH patients (HPAH), and 24 BMPR2 mutation carriers that were as yet unaffected (UMC). Culturing the patient cells removes the signatures of drug effects and inflammation which have made interpretation of results from freshly isolated lymphocytes problematic. We found that gene expression signatures from IPAH patients clustered either with HPAH patients or in a single distinct group. There were no groups of genes changed in IPAH that were not also changed in HPAH. HPAH, IPAH, and UMC had common changes in metabolism, actin dynamics, adhesion, cytokines, metabolism, channels, differentiation, and transcription factors. Common to IPAH and HPAH but not UMC were an upregulation of vesicle trafficking, oxidative/nitrosative stress, and cell cycle genes. The transcription factor MSX1, which is known to regulate BMP signaling, was the most upregulated gene (4×) in IPAH patients. These results suggest that IPAH cases have a shared molecular origin, which is closely related to, but distinct from, HPAH. HPAH and IPAH share the majority of altered signaling pathways, suggesting that treatments developed to target the molecular etiology of HPAH will also be effective against IPAH.