Abstract
Mutations in the gene for the transforming growth factor (TGF)-beta superfamily receptor, bone morphogenetic protein receptor II, underlie heritable forms of pulmonary arterial hypertension (PAH). Aberrant signaling via TGF-beta 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-beta1 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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Blotting, Western
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Bone Morphogenetic Protein Receptors, Type II / metabolism
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Cell Proliferation* / drug effects
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Disease Models, Animal
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Disease Progression
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Enzyme Inhibitors / pharmacology
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Humans
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Hypertension, Pulmonary / drug therapy
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Hypertension, Pulmonary / enzymology*
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Hypertension, Pulmonary / pathology
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Hypertrophy, Right Ventricular / drug therapy
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Image Processing, Computer-Assisted
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Imidazoles / pharmacology
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Immunohistochemistry
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Monocrotaline / toxicity
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Muscle, Smooth, Vascular / drug effects
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Muscle, Smooth, Vascular / metabolism*
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Protein Serine-Threonine Kinases / drug effects
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Protein Serine-Threonine Kinases / metabolism*
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Pulmonary Artery / drug effects
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Pulmonary Artery / metabolism
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Pulmonary Artery / pathology
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Quinoxalines / pharmacology
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Rats
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Receptor, Transforming Growth Factor-beta Type I
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Receptors, Transforming Growth Factor beta / drug effects
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Receptors, Transforming Growth Factor beta / metabolism*
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Reverse Transcriptase Polymerase Chain Reaction
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Smad3 Protein / metabolism
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Transforming Growth Factor beta1 / metabolism
Substances
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6-(2-tert-butyl-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline
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Enzyme Inhibitors
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Imidazoles
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Quinoxalines
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Receptors, Transforming Growth Factor beta
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Smad3 Protein
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Transforming Growth Factor beta1
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Monocrotaline
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Protein Serine-Threonine Kinases
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Bone Morphogenetic Protein Receptors, Type II
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Receptor, Transforming Growth Factor-beta Type I
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TGFBR1 protein, human
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Tgfbr1 protein, rat