生物信息学
BMPR2型
基因签名
血管生成
癌症研究
肺动脉高压
内皮祖细胞
转录组
生物
祖细胞
基因表达
表型
基因
药理学
诱导多能干细胞
医学
内科学
骨形态发生蛋白
细胞生物学
干细胞
生物化学
作者
Mingxia Gu,Michele Donato,Minzhe Guo,Neil Wary,Yifei Miao,Shuai Mao,Toshie Saito,Shoichiro Otsuki,Lingli Wang,Rebecca L. Harper,Silin Sa,Rhiju Das,Marlene Rabinovitch
出处
期刊:Science Translational Medicine
[American Association for the Advancement of Science (AAAS)]
日期:2021-05-05
卷期号:13 (592)
被引量:7
标识
DOI:10.1126/scitranslmed.aba6480
摘要
Pulmonary arterial hypertension (PAH) is a progressive disorder leading to occlusive vascular remodeling. Current PAH therapies improve quality of life but do not reverse structural abnormalities in the pulmonary vasculature. Here, we used high-throughput drug screening combined with in silico analyses of existing transcriptomic datasets to identify a promising lead compound to reverse PAH. Induced pluripotent stem cell-derived endothelial cells generated from six patients with PAH were exposed to 4500 compounds and assayed for improved cell survival after serum withdrawal using a chemiluminescent caspase assay. Subsequent validation of caspase activity and improved angiogenesis combined with data analyses using the Gene Expression Omnibus and Library of Integrated Network-Based Cellular Signatures databases revealed that the lead compound AG1296 was positively associated with an anti-PAH gene signature. AG1296 increased abundance of bone morphogenetic protein receptors, downstream signaling, and gene expression and suppressed PAH smooth muscle cell proliferation. AG1296 induced regression of PA neointimal lesions in lung organ culture and PA occlusive changes in the Sugen/hypoxia rat model and reduced right ventricular systolic pressure. Moreover, AG1296 improved vascular function and BMPR2 signaling and showed better correlation with the anti-PAH gene signature than other tyrosine kinase inhibitors. Specifically, AG1296 up-regulated small mothers against decapentaplegic (SMAD) 1/5 coactivators, cAMP response element-binding protein 3 (CREB3), and CREB5: CREB3 induced inhibitor of DNA binding 1 and downstream genes that improved vascular function. Thus, drug discovery for PAH can be accelerated by combining phenotypic screening with in silico analyses of publicly available datasets.
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