Role of the TGF-beta/Alk5 signaling pathway in monocrotaline-induced pulmonary hypertension.
BACKGROUND
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-beta receptor I, Alk1, have been implicated in the pathogenesis of pulmonary hypertension (PH). However, the role of TGF-beta family signaling in PH and pulmonary vascular remodeling remains unclear.


OBJECTIVE
To determine whether inhibition of TGF-beta signaling will attenuate and reverse monocrotaline-induced PH (MCT-PH).


METHODS
We have used an orally active small-molecule TGF-beta receptor I inhibitor, SD-208, to determine the functional role of this pathway in MCT-PH.


RESULTS
The development of MCT-PH was associated with increased vascular cell apoptosis, which paralleled TGF-beta signaling as documented by psmad2 expression. Inhibition of TGF-beta 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-beta signaling with SD-208 in established MCT-PH resulted in a small but significant improvement in hemodynamic parameters and medial remodeling.


CONCLUSIONS
These findings provide evidence that increased TGF-beta signaling participates in the pathogenesis of experimental severe PH.
Zaiman
Ari L
AL
Johns Hopkins School of Medicine, Division of Pulmonary and Critical Care Medicine, 1830 East Monument Street, 5th Floor, Baltimore, MD 21205, USA. azaiman1@jhmi.edu
Podowski
Megan
M
Medicherla
Satya
S
Gordy
Kimberley
K
Xu
Fang
F
Zhen
Lijie
L
Shimoda
Larissa A
LA
Neptune
Enid
E
Higgins
Linda
L
Murphy
Alison
A
Chakravarty
Sarvajit
S
Protter
Andrew
A
Sehgal
Pravin B
PB
Champion
Hunter C
HC
Tuder
Rubin M
RM
D000818:Animals; D004195:Disease Models, Animal; D042783:Endothelial Cells; D022781:Hepatocytes; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000503:physiopathology*; D008297:Male; D016686:Monocrotaline / Q000008:administration & dosage / Q000633:toxicity; D010936:Plant Extracts / Q000008:administration & dosage / Q000633:toxicity; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000502:physiology*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000502:physiology*; D014407:Tumor Cells, Cultured
D010936:Plant Extracts; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D016686:Monocrotaline; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625843:Tgfbr1 protein, rat