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Published ahead of print on January 17, 2008, doi:10.1164/rccm.200707-1083OC

Am. J. Respir. Crit. Care Med., Volume 177, Number 8, April 2008, 896-905

A more recent version of this article appeared on April 15, 2008
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Submitted on July 23, 2007
Accepted on January 16, 2008

Role of TGF-{beta}/ALK5 kinase 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 Tuder6

1 Division of Pulmonary and Critical Care Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA, 2 Scios Inc., Fremont, CA, USA, 3 Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY, USA, 4 Department of Medicine, Division of Cardiopulmonary Pathology, Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA, 5 Division of Cardiology, Johns Hopkins School of Medicine, Baltimore, MD, USA, 6 Division of Pulmonary and Critical Care Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA; Division of Cardiology, Johns Hopkins School of Medicine, Baltimore, MD, USA

* To whom correspondence should be addressed. E-mail: azaiman1{at}jhmi.edu.

Rationale: Pulmonary arterial hypertension (PAH) 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 TGF signaling pathways, bone morphogenetic protein receptor II (BMPR II) and the TGF-{beta}receptor I, ALK1, have been implicated in the pathogenesis of PH. However, the role of TGF-{beta}family signaling in pulmonary hypertension and pulmonary vascular remodeling remains unclear. Objectives: To determine whether inhibition of TGF {beta}signaling will attenuate and reverse monocrotaline induced pulmonary hypertension. Methods: We have used an orally active small molecule TGF {beta}inhibitor, SD-208, to determine the functional role of this pathway in monocrotaline-induced pulmonary hypertension (MCT-PH). Measurements and main 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 SD208 significantly attenuated the development of the pulmonary hypertension 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 pulmonary hypertension.
Key words: Pulmonary Hypertension, TGF-{beta}, Alk5, Monocrotaline, Apoptosis, Proliferation, Matrix Metalloproteinase




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