Notch1 signalling regulates endothelial proliferation and apoptosis in pulmonary arterial hypertension
Notch1 signalling regulates endothelial proliferation and apoptosis in pulmonary arterial hypertension
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DOI：
10.1183/13993003.00773-2015
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发表时间：
2016-10-01
影响因子：
24.3
通讯作者：
Schermuly, Ralph Theo
中科院分区：
文献类型：
--
作者：
Dabral, Swati;Tian, Xia;Schermuly, Ralph Theo
肺动脉高压（PAH）的特征是过度的肺血管重塑，涉及内膜、中膜以及外膜中细胞的增殖失调。Notch 1在特发性肺动脉高压（IPAH）患者和缺氧/SU 5416（SUHx）大鼠肺组织中的表达均高于健康对照组，但在肺动脉高压（IPAH）患者和缺氧/SU 5416（SUHx）大鼠肺组织中Notch 1的表达均高于健康对照组。体外功能丧失和获得研究表明，Notch 1通过下调p21增加人PAECs（hPAECs）的增殖，并通过Bcl-2和Survivin抑制凋亡。使用γ-分泌酶抑制剂二苯并氮杂卓抑制Notch信号传导剂量依赖性地降低了hPAEC的增殖和迁移。值得注意的是，Notch 1的表达和转录活性增加缺氧条件下的hPAEC和Notch 1的敲低抑制缺氧诱导的细胞增殖。此外，在体内治疗与γ-分泌酶抑制剂（AMG 2008827）显着降低右心室收缩压和右心肥大在SUHx rates. In这里，我们得出结论，Notch 1在PAH中起着关键作用，Notch抑制剂可能是一个有前途的治疗选择PAH。
Pulmonary arterial hypertension (PAH) is characterised by excessive pulmonary vascular remodelling involving deregulated proliferation of cells in intima, media as well as adventitia. Pulmonary arterial endothelial cell (PAEC) hyperproliferation and survival underlies the endothelial pathobiology of the disease.The indispensable involvement of Notch1 in the arterial endothelial phenotype and angiogenesis provides intriguing prospects for its involvement in the pathogenesis of PAH.We observed an increased expression of Notch1 in lungs of idiopathic PAH (IPAH) patients and hypoxia/SU5416 (SUHx) rats compared with healthy subjects. In vitro loss-and gain-of-function studies demonstrated that Notch1 increased proliferation of human PAECs (hPAECs) via downregulation of p21 and inhibited apoptosis via Bcl-2 and Survivin. Inhibition of Notch signalling using the gamma-secretase inhibitor dibenzazepine dose-dependently decreased proliferation and migration of hPAECs. Notably, Notch1 expression and transcriptional activity were increased under hypoxia in hPAECs and knockdown of Notch1 inhibited hypoxia-induced proliferation of the cells. Furthermore, in vivo treatment with a gamma-secretase inhibitor (AMG2008827) significantly reduced the right ventricular systolic pressure and right heart hypertrophy in SUHx rats.Here, we conclude that Notch1 plays a critical role in PAH and Notch inhibitors may be a promising therapeutic option for PAH.