Key role of the endothelial TGF-β/ALK1/endoglin signaling pathway in humans and rodents pulmonary hypertension.
Key role of the endothelial TGF-β/ALK1/endoglin signaling pathway in humans and rodents pulmonary hypertension.
复制标题
DOI：
10.1371/journal.pone.0100310
复制
发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Eddahibi S
中科院分区：
文献类型：
--
作者：
Gore B;Izikki M;Mercier O;Dewachter L;Fadel E;Humbert M;Dartevelle P;Simonneau G;Naeije R;Lebrin F;Eddahibi S
影响转化生长因子-β (TGF-β)超家族受体、激活素受体样激酶(ALK)-1和内啡肽（ENG）的突变发生在肺动脉高压（PAH）患者中。为了确定TGF-β/ALK1/ENG通路是否参与PAH，我们研究了14例特发性PAH （iPAH）患者和15例对照者肺组织和培养的肺动脉平滑肌细胞（PA-SMCs）和肺内皮细胞（PECs）中TGF-β、ALK1、ALK5和ENG的表达。鉴于ENG在PEC中高表达，我们评估了TGF-β对Smad1/5/8和Smad2/3活化以及细胞产生生长因子的影响。最后，我们通过测量ENG缺乏（ENG +/−）和野生型（ENG +/+）小鼠右心室（RV）收缩压（RVSP）、右心室肥厚和肺动脉重塑来研究ENG缺乏对慢性缺氧- ph发展的影响。我们还评估了动物肺血管密度、巨噬细胞浸润和细胞因子表达。与对照组相比，iPAH患者血清和肺部TGF-β水平升高，肺组织中ALK1和ENG表达升高，主要在PECs中。TGF-β细胞孵育导致Smad1/5/8磷酸化，并产生FGF2、PDGFb和内皮素诱导的PA-SMC生长。与野生型相比，Eng+/−型小鼠暴露于慢性缺氧后肺血管密度较低，巨噬细胞浸润无变化，尽管肺中白细胞介素-6和单核细胞趋化蛋白-1的表达较高。TGF-β/ALK1/ENG信号通路通过直接影响PECs导致参与PAH发病的生长因子和炎症细胞因子的产生，在iPAH和实验性缺氧PH中发挥关键作用。
Mutations affecting transforming growth factor-beta (TGF-β) superfamily receptors, activin receptor-like kinase (ALK)-1, and endoglin (ENG) occur in patients with pulmonary arterial hypertension (PAH). To determine whether the TGF-β/ALK1/ENG pathway was involved in PAH, we investigated pulmonary TGF-β, ALK1, ALK5, and ENG expressions in human lung tissue and cultured pulmonary-artery smooth-muscle-cells (PA-SMCs) and pulmonary endothelial cells (PECs) from 14 patients with idiopathic PAH (iPAH) and 15 controls. Seeing that ENG was highly expressed in PEC, we assessed the effects of TGF-β on Smad1/5/8 and Smad2/3 activation and on growth factor production by the cells. Finally, we studied the consequence of ENG deficiency on the chronic hypoxic-PH development by measuring right ventricular (RV) systolic pressure (RVSP), RV hypertrophy, and pulmonary arteriolar remodeling in ENG-deficient (Eng+/−) and wild-type (Eng+/+) mice. We also evaluated the pulmonary blood vessel density, macrophage infiltration, and cytokine expression in the lungs of the animals. Compared to controls, iPAH patients had higher serum and pulmonary TGF-β levels and increased ALK1 and ENG expressions in lung tissue, predominantly in PECs. Incubation of the cells with TGF-β led to Smad1/5/8 phosphorylation and to a production of FGF2, PDGFb and endothelin-inducing PA-SMC growth. Endoglin deficiency protected mice from hypoxic PH. As compared to wild-type, Eng+/− mice had a lower pulmonary vessel density, and no change in macrophage infiltration after exposure to chronic hypoxia despite the higher pulmonary expressions of interleukin-6 and monocyte chemoattractant protein-1. The TGF-β/ALK1/ENG signaling pathway plays a key role in iPAH and experimental hypoxic PH via a direct effect on PECs leading to production of growth factors and inflammatory cytokines involved in the pathogenesis of PAH.
登录
查看更多内容
DOI：
10.1152/ajplung.00534.2007
发表时间：
2008-07-01
影响因子：
4.9
作者：
Ambalavanan, Namasivayam;Nicola, Teodora;Chen, Yiu-Fai
通讯作者：
Chen, Yiu-Fai
影响因子：
15.9
作者：
Izikki, Mohamed;Guignabert, Christophe;Eddahibi, Saadia
通讯作者：
Eddahibi, Saadia
DOI：
10.1152/ajpheart.00254.2009
发表时间：
2010-04-01
影响因子：
4.8
作者：
Rajkumar, Revathi;Konishi, Kazuhisa;Ahmad, Ferhaan
通讯作者：
Ahmad, Ferhaan
影响因子：
4
作者：
Castanares, Cristina;Redondo-Horcajo, Mariano;Rodriguez-Pascual, Fernando
通讯作者：
Rodriguez-Pascual, Fernando
影响因子：
24
作者：
Humbert, M;Morrell, NW;Rabinovitch, M
通讯作者：
Rabinovitch, M