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Published online before print March 28, 2007
Eur Respir J 2007, doi:10.1183/09031936.00138206
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ORIGINAL ARTICLE

The TGF-{beta}/Smad2,3 signalling axis is impaired in experimental pulmonary hypertension

A. Zakrzewicz 1, F.M. Kouri 1, B. Nejman 1, G. Kwapiszewska 1, M. Hecker 1, R. Sandu 1, E. Dony 1, W. Seeger 1, R.T. Schermuly 1, O. Eickelberg 1, R.E. Morty 1*

1 Dept of Internal Medicine, University of Giessen Lung Center, Justus Liebig University, Giessen, Germany

* To whom correspondence should be addressed. E-mail: rory.morty{at}innere.med.uni-giessen.de.


  Abstract

Mutations in genes encoding members of the transforming growth factor (TGF)-{beta} superfamily have been identified in idiopathic forms of pulmonary arterial hypertension (PAH). We asked whether perturbations to the TGF-{beta}/Smad2,3 signalling axis occurred in a monocrotaline (MCT) rodent model of experimental PAH.

Expression of the TGF-{beta} signalling machinery was assessed in the lungs and kidneys of MCT-treated rodents with severe PAH, by semi-quantitative reverse-transcription polymerase chain reaction (RT-PCR), real-time RT-PCR, and immunoblot. TGF-{beta} signalling was assessed in the lungs and in pulmonary artery smooth muscle cells (PASMC) from MCT-treated rodents by Smad2 phosphorylation, expression of the ctgf gene, activation of the serpine promoter in a luciferase reporter system, and by the induction of apoptosis.

The expression of Acvrl1 (a type I TGF-{beta} receptor), Tgfbr2 (the type II TGF-{beta} receptor), endoglin (a type III TGF-{beta} receptor), Smad3 and Smad4; as well as TGF-{beta} signalling and TGF-{beta}-induced apoptosis, were dramatically reduced in the lungs and PASMC, but not the kidneys, of MCT-treated rodents that developed severe PAH.

Our data indicate that the TGF-{beta}/Smad2,3 signalling axis is functionally impaired in MCT-treated rodents with severe PAH, underscoring the potential importance of TGF-{beta}/Smad2,3 signalling in the onset or development of PAH.

Keywords:  Apoptosis, monocrotaline, pulmonary artery smooth muscle cell, transforming growth factor-beta, vascular remodelling




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