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The transforming growth factor-ß/Smad2,3 signalling axis is impaired in experimental pulmonary hypertension

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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