Dysregulated bone morphogenetic protein signaling in monocrotaline-induced pulmonary arterial hypertension.
BACKGROUND
Mutations in the bmpr2 gene, encoding the type II bone morphogenetic protein (BMP) receptor, have been identified in patients with pulmonary arterial hypertension (PAH), implicating BMP signaling in PAH. The aim of this study was to assess BMP signaling and its physiological effects in a monocrotaline (MCT) model of PAH.


RESULTS
Expression of BMP receptors Ib and II, and Smads 4, 5, 6, and 8, was downregulated in lungs but not kidneys of MCT-treated rats. Smad1 phosphorylation and expression of BMP/Smad target genes id1 and id3 was also reduced, although ERK1/2 and p38(MAPK) phosphorylation remained unaffected. BMP receptor and Smad expression, Smad1 phosphorylation, and induction of the BMP/Smad-responsive element of the id1 promoter were reduced in pulmonary artery smooth muscle cells (PASMCs) from MCT-treated rats. As a consequence of impaired BMP/Smad signaling, PASMCs from MCT-treated rats were resistant to apoptosis induced by BMP-4 and BMP-7, and were also resistant to BMP-4 antagonism of proliferation induced by platelet-derived growth factor.


CONCLUSIONS
BMP signaling and BMP-regulated physiological phenomena are perturbed in MCT-treated rats, lending solid support to the proposed roles for BMP signaling in the pathogenesis of human PAH.
Morty
Rory E
RE
Department of Internal Medicine, University of Giessen Lung Center, Justus Liebig University, Aulweg 123 (Raum 6-11), D-35392 Giessen, Germany. rory.morty@innere.med.uni-giessen.de
Nejman
Bozena
B
Kwapiszewska
Grazyna
G
Hecker
Matthias
M
Zakrzewicz
Anka
A
Kouri
Fotini M
FM
Peters
Dorothea M
DM
Dumitrascu
Rio
R
Seeger
Werner
W
Knaus
Petra
P
Schermuly
Ralph T
RT
Eickelberg
Oliver
O
D000818:Animals; D017209:Apoptosis; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000235:genetics* / Q000378:metabolism; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics* / Q000378:metabolism; D049109:Cell Proliferation; D004195:Disease Models, Animal; D018450:Disease Progression; D015536:Down-Regulation; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D015151:Immunoblotting; D007150:Immunohistochemistry; D008297:Male; D016686:Monocrotaline / Q000633:toxicity; D016133:Polymerase Chain Reaction; D011651:Pulmonary Artery / Q000378:metabolism / Q000473:pathology; D012313:RNA / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D051901:Smad4 Protein / Q000235:genetics / Q000378:metabolism; D051902:Smad5 Protein / Q000235:genetics / Q000378:metabolism; D051905:Smad6 Protein / Q000235:genetics / Q000378:metabolism; D051904:Smad8 Protein / Q000235:genetics / Q000378:metabolism
D051901:Smad4 Protein; C490811:Smad4 protein, rat; D051902:Smad5 Protein; C497799:Smad5 protein, rat; D051905:Smad6 Protein; C497804:Smad6 protein, rat; D051904:Smad8 Protein; C109462:Smad9 protein, rat; D012313:RNA; D016686:Monocrotaline; D052005:Bone Morphogenetic Protein Receptors, Type I; D052006:Bone Morphogenetic Protein Receptors, Type II