Published online before print January 19, 2009, doi: 10.1161/CIRCULATIONAHA.108.821504
(Circulation. 2009;119:566-576.)
© 2009 American Heart Association, Inc.
Vascular Medicine |
Altered Bone Morphogenetic Protein and Transforming Growth Factor-β Signaling in Rat Models of Pulmonary Hypertension
Potential for Activin Receptor-Like Kinase-5 Inhibition in Prevention and Progression of Disease
From the Department of Medicine (L.L., A.C., X.Y., M.S., P.D.U., N.W.M.), University of Cambridge School of Clinical Medicine, Addenbrooke’s and Papworth Hospitals, Cambridge, United Kingdom, and College of Pharmacy (D.-K.K.), Ewha Womans University, Seoul, Korea.
Correspondence to Professor Nicholas W. Morrell, Division of Respiratory Medicine, Department of Medicine, Box 157, Addenbrooke’s Hospital, Hills Rd, Cambridge CB2 2QQ, United Kingdom. E-mail nwm23{at}cam.ac.uk
Received June 13, 2008; accepted November 13, 2008.
Background— Recent genetic studies have highlighted the role of the bone morphogenetic protein (BMP)/transforming growth factor (TGF)-β 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.
Methods and Results— We studied BMP/TGF-β 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-β activity, again more marked in the monocrotaline model, as evidenced by increased phospho-Smad2/3 and increased expression of TGF-β–regulated genes. Immunohistochemistry revealed increased TGF-β1 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-β stimulated migration of distal rat pulmonary artery smooth muscle cells and that this effect was inhibited by IN-1233.
Conclusions— Disruption of BMP/TGF-β signaling is more pronounced in the monocrotaline model of PAH than in the chronic hypoxia model. Increased TGF-β activity is associated with greater macrophage recruitment with monocrotaline treatment. Inhibition of TGF-β 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.
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