ArticleScience translational medicine2021
iPSC-endothelial cell phenotypic drug screening and in silico analyses identify tyrphostin-AG1296 for pulmonary arterial hypertension.
Article in Science translational medicine, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 42 citations in OpenAlex.
- Human iPSC-Derived Vascularised Lung Organoids for Modelling COPD and Pulmonary Hypertension.Cell proliferation · 2026Article
- Review
- iPSC-Derived Endothelial Cells as Experimental Models for Predictive and Personalized Strategies in Cardiovascular and Cerebrovascular Disease.International journal of molecular sciences · 2026Review
- Advances in porcine stem cell research and their applications in agriculture.Frontiers in cell and developmental biology · 2026Review
- Smarter stem cells: how AI is supercharging iPSC technology.Cell and tissue research · 2025Review
- MTHFR variant links homocysteine metabolism and endothelial cell dysfunction by targeting mitophagy in human thoracic aortic dissection patient induced pluripotent stem cell (iPSC) models.Journal of advanced research · 2025Article
- Role of BMPR2 Mutation in Lung Organoid Differentiation.Biomedicines · 2025Article
- Decreased PECAM-1 May be a potential pathological factor for vascular injury in T2DM patients.Scientific reports · 2025Article
- Umbilical Cord-Mesenchymal Stromal Cell-Derived Extracellular Vesicles Target the Liver to Improve Neurovascular Health in Type 2 Diabetes With Non-Alcoholic Fatty Liver Disease.Journal of extracellular vesicles · 2025Article
- High Shear Stress Reduces ERG Causing Endothelial-Mesenchymal Transition and Pulmonary Arterial Hypertension.Arteriosclerosis, thrombosis, and vascular biology · 2025Article
- Emerging biomaterials and bio-nano interfaces in pulmonary hypertension therapy: transformative strategies for personalized treatment.Frontiers in bioengineering and biotechnology · 2025Review
- Clinical trials in-a-dish for cardiovascular medicine.European heart journal · 2024Review
- Pathology and pathobiology of pulmonary hypertension: current insights and future directions.The European respiratory journal · 2024Review
- Tissue-Engineered Microvessels: A Review of Current Engineering Strategies and Applications.Advanced healthcare materials · 2024Review
- Sources and applications of endothelial seed cells: a review.Stem cell research & therapy · 2024Review
- Novel insights into the potential applications of stem cells in pulmonary hypertension therapy.Respiratory research · 2024Review
- Induced pluripotent stem cells (iPSCs): molecular mechanisms of induction and applications.Signal transduction and targeted therapy · 2024Review
- Harnessing human genetics and stem cells for precision cardiovascular medicine.Cell genomics · 2024Review
- Understanding genomic medicine for thoracic aortic disease through the lens of induced pluripotent stem cells.Frontiers in cardiovascular medicine · 2024Review
- Bioinformatics analyses and experimental validation of ferroptosis-related genes in bronchopulmonary dysplasia pathogenesis.PloS one · 2024Article
Corrections and comments
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Authors and funding
13 authors at 3 institutions in 3 countries.
Funding
Abstract
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.