title: Notch1 signalling regulates endothelial proliferation and apoptosis in pulmonary arterial hypertension.
abstract: 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 γ-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 γ-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.
authors.affiliation: Max Planck Institute for Heart and Lung Research, Member of the German Center for Lung Research (DZL), Bad Nauheim, Germany.
authors.forename: Swati
authors.initials: S
authors.lastname: Dabral
authors.affiliation: Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research (DZL), Giessen, Germany.
authors.forename: Xia
authors.initials: X
authors.lastname: Tian
authors.affiliation: Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research (DZL), Giessen, Germany.
authors.forename: Baktybek
authors.initials: B
authors.lastname: Kojonazarov
authors.affiliation: Max Planck Institute for Heart and Lung Research, Member of the German Center for Lung Research (DZL), Bad Nauheim, Germany Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research (DZL), Giessen, Germany.
authors.forename: Rajkumar
authors.initials: R
authors.lastname: Savai
authors.affiliation: Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research (DZL), Giessen, Germany.
authors.forename: Hossein Ardeschir
authors.initials: HA
authors.lastname: Ghofrani
authors.affiliation: Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research (DZL), Giessen, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Weissmann
authors.affiliation: Cardiometabolic Disorders, Amgen, Thousand Oaks, CA, USA.
authors.forename: Monica
authors.initials: M
authors.lastname: Florio
authors.affiliation: Department of Oncology Research, Amgen, Thousand Oaks, CA, USA.
authors.forename: Jan
authors.initials: J
authors.lastname: Sun
authors.affiliation: Institute of Pathology, Hannover Medical School, Member of the German Center for Lung Research (DZL), Hannover, Germany.
authors.forename: Danny
authors.initials: D
authors.lastname: Jonigk
authors.affiliation: Institute of Pathology, Hannover Medical School, Member of the German Center for Lung Research (DZL), Hannover, Germany.
authors.forename: Lavinia
authors.initials: L
authors.lastname: Maegel
authors.affiliation: Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research (DZL), Giessen, Germany.
authors.forename: Friedrich
authors.initials: F
authors.lastname: Grimminger
authors.affiliation: Max Planck Institute for Heart and Lung Research, Member of the German Center for Lung Research (DZL), Bad Nauheim, Germany Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research (DZL), Giessen, Germany.
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.affiliation: Max Planck Institute for Heart and Lung Research, Member of the German Center for Lung Research (DZL), Bad Nauheim, Germany Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research (DZL), Giessen, Germany.
authors.forename: Soni
authors.initials: S
authors.lastname: Savai Pullamsetti
authors.affiliation: Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research (DZL), Giessen, Germany Ralph.schermuly@innere.med.uni-giessen.de.
authors.forename: Ralph Theo
authors.initials: RT
authors.lastname: Schermuly
mesh_terms: D000818:Animals; D017209:Apoptosis; D016022:Case-Control Studies; D015687:Cell Hypoxia; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D015536:Down-Regulation; D004452:Echocardiography; D004730:Endothelium, Vascular / Q000473:pathology*; D065627:Familial Primary Pulmonary Hypertension; D057809:HEK293 Cells; D006801:Humans; D006984:Hypertrophy; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D009389:Neovascularization, Pathologic; D010641:Phenotype; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D051881:Receptor, Notch1 / Q000378:metabolism*; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction; D000077022:Survivin; D014158:Transcription, Genetic
chemical_list: C000595707:BCL2 protein, human; C107489:BIRC5 protein, human; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D051034:Inhibitor of Apoptosis Proteins; C497761:NOTCH1 protein, human; C497763:Notch1 protein, rat; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D051881:Receptor, Notch1; D051880:Receptors, Notch; D000077022:Survivin