GSE169045 iPSC-endothelial cell phenotypic drug screening and in silico analyses identify tyrphostin AG1296 for pulmonary arterial hypertension

Contributors : Mingxia Gu ; Michele Donato ; Minzhe GuoSeries Type : Expression profiling by high throughput sequencingOrganism : Homo sapiensPulmonary 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 a high-throughput drug screen 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 (iPSC-EC) generated from six patients with PAH were exposed to 4,500 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 in silico analyses using the Gene Expression Omnibus (GEO  ) and Library of Integrated Network-Based Cellular Signatures (LINCS) databases revealed that the lead compound AG1296 was positively associated with an anti-PAH gene signature. AG1296 increased abundance of bone morphogenetic protein receptors (BMPR2 and Ia), downstream signaling and gene express ion, and suppressed PAH smooth muscle cell proliferation. AG1296 induced regression of pulmonary arterial (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 v...
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Expression profiling by high throughput sequencing Homo sapiens Source Type: research