English
 
Help Privacy Policy Disclaimer
  Advanced SearchBrowse

Item

ITEM ACTIONSEXPORT
  Notch1 signalling regulates endothelial proliferation and apoptosis in pulmonary arterial hypertension

Dabral, S., Tian, X., Kojonazarov, B., Savai, R., Ghofrani, H. A., Weissmann, N., et al. (2016). Notch1 signalling regulates endothelial proliferation and apoptosis in pulmonary arterial hypertension. EUROPEAN RESPIRATORY JOURNAL, 48(4), 1137-1149. doi:10.1183/13993003.00773-2015.

Item is

Basic

show hide
Genre: Journal Article

Files

show Files

Locators

show

Creators

show
hide
 Creators:
Dabral, Swati1, Author              
Tian, Xia, Author
Kojonazarov, Baktybek, Author
Savai, Rajkumar1, Author              
Ghofrani, Hossein Ardeschir, Author
Weissmann, Norbert, Author
Florio, Monica, Author
Sun, Jan, Author
Jonigk, Danny, Author
Maegel, Lavinia, Author
Grimminger, Friedrich, Author
Seeger, Werner1, Author              
Pullamsetti, Soni Savai1, Author              
Schermuly, Ralph Theo, Author
Affiliations:
1Lung Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society, ou_2591698              

Content

show
hide
Free keywords: SMOOTH-MUSCLE-CELLS; PLEXIFORM LESIONS; TRANSCRIPTION FACTOR; GROWTH-FACTOR; NEOINTIMAL FORMATION; ANGIOGENESIS; INHIBITION; EXPRESSION; SURVIVIN; CANCERRespiratory System;
 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 gamma-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 gamma-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.

Details

show
hide
Language(s): eng - English
 Dates: 2016
 Publication Status: Published in print
 Pages: 13
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Degree: -

Event

show

Legal Case

show

Project information

show

Source 1

show
hide
Title: EUROPEAN RESPIRATORY JOURNAL
Source Genre: Journal
 Creator(s):
Affiliations:
Publ. Info: 442 GLOSSOP RD, SHEFFIELD S10 2PX, ENGLAND : EUROPEAN RESPIRATORY SOC JOURNALS LTD
Pages: - Volume / Issue: 48 (4) Sequence Number: - Start / End Page: 1137 - 1149 Identifier: ISSN: 0903-1936