TY - JOUR
T1 - Dysregulated bone morphogenetic protein signaling in monocrotaline-induced pulmonary arterial hypertension
AU - Morty, Rory E.
AU - Nejman, Bozena
AU - Kwapiszewska, Grazyna
AU - Hecker, Matthias
AU - Zakrzewicz, Anka
AU - Kouri, Fotini M.
AU - Peters, Dorothea M.
AU - Dumitrascu, Rio
AU - Seeger, Werner
AU - Knaus, Petra
AU - Schermuly, Ralph T.
AU - Eickelberg, Oliver
PY - 2007/5
Y1 - 2007/5
N2 - 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. METHODS AND 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 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. CONCLUSION - 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.
AB - 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. METHODS AND 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 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. CONCLUSION - 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.
KW - Bone morphogenetic proteins
KW - Monocrotaline
KW - Pulmonary arterial hypertension
KW - Smad
KW - VSMC proliferation
KW - Vascular remodeling
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U2 - 10.1161/ATVBAHA.107.141200
DO - 10.1161/ATVBAHA.107.141200
M3 - Article
C2 - 17347486
AN - SCOPUS:34247387518
SN - 1079-5642
VL - 27
SP - 1072
EP - 1078
JO - Arteriosclerosis, thrombosis, and vascular biology
JF - Arteriosclerosis, thrombosis, and vascular biology
IS - 5
ER -