title: 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.
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.
authors.affiliation: Respiratory Disease Area, Novartis Horsham Research Centre, Horsham, West Sussex, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Thomas
authors.forename: Cerys
authors.initials: C
authors.lastname: Docx
authors.forename: Alan M
authors.initials: AM
authors.lastname: Holmes
authors.forename: Sarah
authors.initials: S
authors.lastname: Beach
authors.forename: Nicholas
authors.initials: N
authors.lastname: Duggan
authors.forename: Karen
authors.initials: K
authors.lastname: England
authors.forename: Catherine
authors.initials: C
authors.lastname: Leblanc
authors.forename: Clemence
authors.initials: C
authors.lastname: Lebret
authors.forename: Francis
authors.initials: F
authors.lastname: Schindler
authors.forename: Farheen
authors.initials: F
authors.lastname: Raza
authors.forename: Christoph
authors.initials: C
authors.lastname: Walker
authors.forename: Alexi
authors.initials: A
authors.lastname: Crosby
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: Davies
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Morrell
authors.forename: David C
authors.initials: DC
authors.lastname: Budd
mesh_terms: D000818:Animals; D015153:Blotting, Western; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D017380:Hypertrophy, Right Ventricular / Q000188:drug therapy; D007091:Image Processing, Computer-Assisted; D007093:Imidazoles / Q000494:pharmacology; D007150:Immunohistochemistry; D016686:Monocrotaline / Q000633:toxicity; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism*; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000187:drug effects / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051900:Smad3 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: C521813:6-(2-tert-butyl-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline; D004791:Enzyme Inhibitors; D007093:Imidazoles; D011810:Quinoxalines; D018125:Receptors, Transforming Growth Factor beta; D051900:Smad3 Protein; D053773:Transforming Growth Factor beta1; D016686:Monocrotaline; D017346:Protein Serine-Threonine Kinases; D052006:Bone Morphogenetic Protein Receptors, Type II; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human; C000625843:Tgfbr1 protein, rat