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Published ahead of print on January 17, 2008, doi:10.1164/rccm.200707-1083OC
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American Journal of Respiratory and Critical Care Medicine Vol 177. pp. 896-905, (2008)
© 2008 American Thoracic Society
doi: 10.1164/rccm.200707-1083OC


Original Article

Role of the TGF-β/Alk5 Signaling Pathway in Monocrotaline-induced Pulmonary Hypertension

Ari L. Zaiman1, Megan Podowski1, Satya Medicherla2, Kimberley Gordy1, Fang Xu3, Lijie Zhen4, Larissa A. Shimoda1, Enid Neptune1, Linda Higgins2, Alison Murphy2, Sarvajit Chakravarty2, Andrew Protter2, Pravin B. Sehgal3, Hunter C. Champion5 and Rubin M. Tuder1,5

1 Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland; 2 Scios, Inc., Fremont, California; 3 Department Cell Biology and Anatomy, New York Medical College, Valhalla, New York; and 4 Division of Cardiopulmonary Pathology, Department of Pathology, and 5 Division of Cardiology, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland

Correspondence and requests for reprints should be addressed to Ari L. Zaiman, M.D., Ph.D., Johns Hopkins School of Medicine, Division of Pulmonary and Critical Care Medicine, 1830 East Monument Street, 5th Floor, Baltimore, MD 21205. E-mail: azaiman1{at}jhmi.edu

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 MCT-PH 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.

Key Words: pulmonary hypertension • transforming growth factor-β • apoptosis • proliferation • matrix metalloproteinase


AT A GLANCE COMMENTARY

Scientific Knowledge on the Subject
Transforming growth factor (TGF)-β signaling pathways have been implicated in the pathogenesis of pulmonary hypertension (PH); however, the mechanism by which altered signaling leads to PH is unknown. To understand its role, animal models have been used, but the level of TGF-β varies.

What This Study Adds to the Field
Increased TGF-β signaling participates in the pathogenesis of experimental severe PH.

 



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