Published online before print December 30, 2008

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(American Journal of Pathology. 2009;174:380-389.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.080565

Activin-Like Kinase 5 (ALK5) Mediates Abnormal Proliferation of Vascular Smooth Muscle Cells from Patients with Familial Pulmonary Arterial Hypertension and Is Involved in the Progression of Experimental Pulmonary Arterial Hypertension Induced by Monocrotaline

Matthew Thomas^*, Cerys Docx^*, Alan M. Holmes^*, Sarah Beach^*, Nicholas Duggan^*, Karen England^*, Catherine Leblanc, Clemence Lebret^*, Francis Schindler^*, Farheen Raza^*, Christoph Walker^*, Alexi Crosby, Rachel J. Davies, Nicholas W. Morrell and David C. Budd^*

From the Respiratory Disease Area^* and Global Discovery Chemistry, Novartis Horsham Research Centre, Horsham; and the Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke’s and Papworth Hospitals, Cambridge, United Kingdom

Mutations in the gene for the transforming growth factor (TGF)-β superfamily receptor, bone morphogenetic protein receptor II, underlie heritable forms of pulmonary arterial hypertension (PAH). Aberrant signaling via TGF-β receptor I/activin receptor-like kinase 5 may be important for both the development and progression of PAH. We investigated the therapeutic potential of a well-characterized and potent activin receptor-like kinase 5 inhibitor, SB525334 [6-(2-tert-butyl-5-{6-methyl-pyridin-2-yl}-1H-imidazol-4-yl)-quinoxaline] for the treatment of PAH. In this study, we demonstrate that pulmonary artery smooth muscle cells from patients with familial forms of idiopathic PAH exhibit heightened sensitivity to TGF-β1 in vitro, which can be attenuated after the administration of SB525334. We further demonstrate that SB525334 significantly reverses pulmonary arterial pressure and inhibits right ventricular hypertrophy in a rat model of PAH. Immunohistochemical studies confirmed a significant reduction in pulmonary arteriole muscularization induced by monocrotaline (used experimentally to induce PAH) after treatment of rats with SB525334. Collectively, these data are consistent with a role for the activin receptor-like kinase 5 in the progression of idiopathic PAH and imply that strategies to inhibit activin receptor-like kinase 5 signaling may have therapeutic benefit.