TY - JOUR
T1 - Role of the TGF-β/Alk5 signaling pathway in monocrotaline-induced pulmonary hypertension
AU - Zaiman, Ari L.
AU - Podowski, Megan
AU - Medicherla, Satya
AU - Gordy, Kimberley
AU - Xu, Fang
AU - Zhen, Lijie
AU - Shimoda, Larissa A.
AU - Neptune, Enid
AU - Higgins, Linda
AU - Murphy, Alison
AU - Chakravarty, Sarvajit
AU - Protter, Andrew
AU - Sehgal, Pravin B.
AU - Champion, Hunter C.
AU - Tuder, Rubin M.
PY - 2008/4/15
Y1 - 2008/4/15
N2 - Rationale: Pulmonary arterial hypertension is a progressive disease characterized by an elevation in the mean pulmonary artery pressure leading to right heart failure and a significant risk of death. Alterations in two transforming growth factor (TGF) signaling pathways, bone morphogenetic protein receptor II and the TGF-β receptor I, Alk1, have been implicated in the pathogenesis of pulmonary hypertension (PH). However, the role of TGF-β family signaling in PH and pulmonary vascular remodeling remains unclear. Objectives: To determine whether inhibition of TGF-β signaling will attenuate and reverse monocrotaline-induced PH (MCT-PH). Methods: We have used an orally active small-molecule TGF-β receptor I inhibitor, SD-208, to determine the functional role of this pathway in MCT-PH. Measurements and Main Results: The development of MCT-PH was associated with increased vascular cell apoptosis, which paralleled TGF-β signaling as documented by psmad2 expression. Inhibition of TGF-β signaling with SD-208 significantly attenuated the development of the PH and reduced pulmonary vascular remodeling. These effects were associated with decreased early vascular cell apoptosis, adventitial cell proliferation, and matrix metalloproteinase expression. Inhibition of TGF-β signaling with SD-208 in established MCTPH resulted in a small but significant improvement in hemodynamic parameters and medial remodeling. Conclusions: These findings provide evidence that increased TGF-β signaling participates in the pathogenesis of experimental severe PH.
AB - Rationale: Pulmonary arterial hypertension is a progressive disease characterized by an elevation in the mean pulmonary artery pressure leading to right heart failure and a significant risk of death. Alterations in two transforming growth factor (TGF) signaling pathways, bone morphogenetic protein receptor II and the TGF-β receptor I, Alk1, have been implicated in the pathogenesis of pulmonary hypertension (PH). However, the role of TGF-β family signaling in PH and pulmonary vascular remodeling remains unclear. Objectives: To determine whether inhibition of TGF-β signaling will attenuate and reverse monocrotaline-induced PH (MCT-PH). Methods: We have used an orally active small-molecule TGF-β receptor I inhibitor, SD-208, to determine the functional role of this pathway in MCT-PH. Measurements and Main Results: The development of MCT-PH was associated with increased vascular cell apoptosis, which paralleled TGF-β signaling as documented by psmad2 expression. Inhibition of TGF-β signaling with SD-208 significantly attenuated the development of the PH and reduced pulmonary vascular remodeling. These effects were associated with decreased early vascular cell apoptosis, adventitial cell proliferation, and matrix metalloproteinase expression. Inhibition of TGF-β signaling with SD-208 in established MCTPH resulted in a small but significant improvement in hemodynamic parameters and medial remodeling. Conclusions: These findings provide evidence that increased TGF-β signaling participates in the pathogenesis of experimental severe PH.
KW - Apoptosis
KW - Matrix metalloproteinase
KW - Proliferation
KW - Pulmonary hypertension
KW - Transforming growth factor-β
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U2 - 10.1164/rccm.200707-1083OC
DO - 10.1164/rccm.200707-1083OC
M3 - Article
C2 - 18202349
AN - SCOPUS:42649136572
SN - 1073-449X
VL - 177
SP - 896
EP - 905
JO - American journal of respiratory and critical care medicine
JF - American journal of respiratory and critical care medicine
IS - 8
ER -