@article {Xing1702229, author = {Yanjiang Xing and Shuang Zhao and Qingxia Wei and Shiqiang Gong and Xin Zhao and Fang Zhou and Rafia AI-Lamki and Daniel Ortmann and Mingxia Du and Roger Pedersen and Guangdong Shang and Shuyi Si and Nicholas W Morrell and Jun Yang}, title = {A novel piperidine identified by stem cell based screening attenuates pulmonary arterial hypertension via regulating BMP2 and PTGS2 levels}, elocation-id = {1702229}, year = {2018}, doi = {10.1183/13993003.02229-2017}, publisher = {European Respiratory Society}, abstract = {Genetic defects in bone morphogenetic protein type-II receptor (BMPRII) signalling and inflammation contribute to the pathogenesis of pulmonary arterial hypertension (PAH). The receptor is activated by BMP ligands, which also enhance BMPR2 transcription. A small molecule BMP upregulator with selectivity on vascular endothelium would represent a desirable therapeutic intervention for PAH.We assayed compounds identified in the screening of BMP2 upregulators for their ability to increase expression of Inhibitor of DNA binding 1 (Id1), using a dual reporter driven specifically in human embryonic stem cell (hESC)-derived endothelial cells (ECs). These assays identified a novel piperidine (BMP upregulator 1, BUR1) with half-maximal effective concentration (EC50) of 0.098 μmol/L to increase endothelial Id1 expression. Microarray analyses and immunoblotting showed that BUR1 induced BMP2 and PTGS2 expression. BUR1 effectively rescued deficient angiogenesis in autologous BMPR2+/R899X ECs generated by CRISPR/Cas9 and patient cells.BUR1 prevented and reversed PAH in monocrotaline (MCT) rats, it also restored BMPRII downstream signalling and modulated arachidonic acid pathway in the pulmonary arterial endothelium in Sugen 5416/hypoxia PAH model.In conclusion, using stem cell technology we provide a novel small molecule compound that regulates BMP2 and PTGS2 levels which might be useful for the treatment of PAH.Using stem cell technology we provide a novel small molecule compound that regulates BMP2 and PTGS2 levels for PAHFootnotesThis manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.Conflict of interest: Dr. Xing has nothing to disclose.Conflict of interest: Dr. Zhao has nothing to disclose.Conflict of interest: Dr. Qingxia has nothing to disclose.Conflict of interest: Dr. Gong has nothing to disclose.Conflict of interest: Dr. Zhao has nothing to disclose.Conflict of interest: Dr. Zhou has nothing to disclose.Conflict of interest: Dr. Al-Lamki has nothing to disclose.Conflict of interest: Dr. Ortmann has nothing to disclose.Conflict of interest: Dr. Du has nothing to disclose.Conflict of interest: Dr. Pedersen has nothing to disclose.Conflict of interest: Dr. Shang has nothing to disclose.Conflict of interest: Dr. Si has nothing to disclose.Conflict of interest: Dr. Morrell has nothing to disclose.Conflict of interest: Dr. Yang has nothing to disclose.}, issn = {0903-1936}, URL = {https://erj.ersjournals.com/content/early/2018/02/08/13993003.02229-2017}, eprint = {https://erj.ersjournals.com/content/early/2018/02/08/13993003.02229-2017.full.pdf}, journal = {European Respiratory Journal} }