Published online before print
March 28, 2007, 10.1183/09031936.00138206
Eur Respir J 2007; 29:1094-1104
Copyright ©ERS Journals Ltd 2007
The transforming growth factor-ß/Smad2,3 signalling axis is impaired in experimental pulmonary hypertension
A. Zakrzewicz,
F. M. Kouri,
B. Nejman,
G. Kwapiszewska,
M. Hecker,
R. Sandu,
E. Dony,
W. Seeger,
R. T. Schermuly,
O. Eickelberg and
R. E. Morty
Dept of Internal Medicine, University of Giessen Lung Center, Justus Liebig University, Giessen, Germany.
CORRESPONDENCE: R. E. Morty, Dept of Internal Medicine, University of Giessen Lung Center, Justus Liebig University, Aulweg 123 (Raum 6-11), D-35392 Giessen, Germany. Fax: 49 6419942308. E-mail: rory.morty{at}innere.med.uni-giessen.de
Keywords: Apoptosis, monocrotaline, pulmonary artery smooth muscle cells, transforming growth factor-ß, vascular remodelling
Received: October 24, 2006
Accepted March 14, 2007
Mutations in genes encoding members of the transforming growth factor (TGF)-ß superfamily have been identified in idiopathic forms of pulmonary arterial hypertension (PAH). The current study examined whether perturbations to the TGF-ß/Smad2,3 signalling axis occurred in a monocrotaline (MCT) rodent model of experimental PAH.
Expression of the TGF-ß signalling machinery was assessed in the lungs and kidneys of MCT-treated rodents with severe PAH by semi-quantitative reverse-transcription (RT)-PCR, real-time RT-PCR and immunoblotting. TGF-ß signalling was assessed in the lungs and in pulmonary artery smooth muscle cells (PASMC) from MCT-treated rodents by Smad2 phosphorylation, expression of the connective tissue growth factor gene, activation of the serpine promoter in a luciferase reporter system and by the induction of apoptosis.
The expression of type1 TGF-ß receptor (TGFBR) activin-A receptor-like kinase1, TGFBR-2, TGFBR-3 (endoglin), Smad3 and Smad4; as well as TGF-ß signalling and TGF-ß-induced apoptosis, were dramatically reduced in the lungs and PASMC, but not the kidneys, of MCT-treated rodents that developed severe PAH.
The current data indicate that the transforming growth factor-ß/Smad2,3 signalling axis is functionally impaired in monocrotaline-treated rodents with severe pulmonary arterial hypertension, underscoring the potential importance of transforming growth factor-ß/Smad2,3 signalling in the onset or development of pulmonary arterial hypertension.
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Copyright © 2007 by the European Respiratory Society.
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