Altered bone morphogenetic protein and transforming growth factor-beta signaling in rat models of pulmonary hypertension: potential for activin receptor-like kinase-5 inhibition in prevention and progression of disease.
BACKGROUND
Recent genetic studies have highlighted the role of the bone morphogenetic protein (BMP)/transforming growth factor (TGF)-beta signaling pathways in the pathogenesis of familial pulmonary arterial hypertension (PAH). It remains unclear whether alterations in these pathways contribute to other forms of pulmonary hypertension and to what extent these changes can be exploited for therapeutic intervention.


RESULTS
We studied BMP/TGF-beta signaling in 2 rat models of PAH due to chronic hypoxia and monocrotaline. In both models, there was a significant reduction in lung BMP type IA receptor and BMP type II receptor mRNA expression, although these changes were more pronounced in the monocrotaline model. This was accompanied by a reduction in lung levels of phospho-Smad1/5 and Id (inhibitor of DNA binding) gene expression in the monocrotaline model. In contrast, we observed increased TGF-beta activity, again more marked in the monocrotaline model, as evidenced by increased phospho-Smad2/3 and increased expression of TGF-beta-regulated genes. Immunohistochemistry revealed increased TGF-beta(1) expression in pulmonary artery smooth muscle cells and macrophages surrounding remodeled pulmonary arteries in monocrotaline rats. Inhibition of activin receptor-like kinase-5 signaling in vivo with the selective small-molecule inhibitor IN-1233 prevented PAH, right ventricular hypertrophy, and vascular remodeling after monocrotaline injection and inhibited the progression of established PAH in this model. No significant effect was observed in hypoxic PAH. In vitro studies confirmed that TGF-beta stimulated migration of distal rat pulmonary artery smooth muscle cells and that this effect was inhibited by IN-1233.


CONCLUSIONS
Disruption of BMP/TGF-beta signaling is more pronounced in the monocrotaline model of PAH than in the chronic hypoxia model. Increased TGF-beta activity is associated with greater macrophage recruitment with monocrotaline treatment. Inhibition of TGF-beta signaling via activin receptor-like kinase-5 prevents development and progression of PAH in the monocrotaline model and may involve inhibition of pulmonary artery smooth muscle cell migration.
Long
Lu
L
Division of Respiratory Medicine, Department of Medicine, Box 157, Addenbrooke's Hospital, Hills Rd, Cambridge CB2 2QQ, United Kingdom.
Crosby
Alexi
A
Yang
Xudong
X
Southwood
Mark
M
Upton
Paul D
PD
Kim
Dae-Kee
DK
Morrell
Nicholas W
NW
D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics / Q000378:metabolism*; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D002908:Chronic Disease; D004195:Disease Models, Animal; D018450:Disease Progression; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism*; D000860:Hypoxia / Q000378:metabolism / Q000473:pathology; D008297:Male; D016686:Monocrotaline; D009131:Muscle, Smooth, Vascular / Q000201:enzymology / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D011804:Quinolines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000378:metabolism*
C538835:3-((4-(6-methylpyridin-2-yl)-5-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)benzamide; D001549:Benzamides; D019485:Bone Morphogenetic Proteins; D011804:Quinolines; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D016686:Monocrotaline; D017346:Protein Serine-Threonine Kinases; D052006:Bone Morphogenetic Protein Receptors, Type II; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625843:Tgfbr1 protein, rat