The transforming growth factor-beta/Smad2,3 signalling axis is impaired in experimental pulmonary hypertension.
Mutations in genes encoding members of the transforming growth factor (TGF)-beta superfamily have been identified in idiopathic forms of pulmonary arterial hypertension (PAH). The current study examined 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 (RT)-PCR, real-time RT-PCR and immunoblotting. 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 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-beta receptor (TGFBR) activin-A receptor-like kinase1, TGFBR-2, TGFBR-3 (endoglin), 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. The current data indicate that the transforming growth factor-beta/Smad2,3 signalling axis is functionally impaired in monocrotaline-treated rodents with severe pulmonary arterial hypertension, underscoring the potential importance of transforming growth factor-beta/Smad2,3 signalling in the onset or development of pulmonary arterial hypertension.
Zakrzewicz
A
A
Department of Internal Medicine, University of Giessen Lung Center, Giessen, Germany.
Kouri
F M
FM
Nejman
B
B
Kwapiszewska
G
G
Hecker
M
M
Sandu
R
R
Dony
E
E
Seeger
W
W
Schermuly
R T
RT
Eickelberg
O
O
Morty
R E
RE
D000818:Animals; D017209:Apoptosis; D004195:Disease Models, Animal; D006976:Hypertension, Pulmonary / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000473:pathology; D008954:Models, Biological; D016686:Monocrotaline / Q000494:pharmacology; D009154:Mutation; D011651:Pulmonary Artery / Q000473:pathology; D051381:Rats; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction; D051899:Smad2 Protein / Q000235:genetics*; D051900:Smad3 Protein / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D018125:Receptors, Transforming Growth Factor beta; D051899:Smad2 Protein; C497784:Smad2 protein, rat; D051900:Smad3 Protein; C497787:Smad3 protein, rat; D016212:Transforming Growth Factor beta; D016686:Monocrotaline