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.
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.
Thomas
Matthew
M
Respiratory Disease Area, Novartis Horsham Research Centre, Horsham, West Sussex, UK.
Docx
Cerys
C
Holmes
Alan M
AM
Beach
Sarah
S
Duggan
Nicholas
N
England
Karen
K
Leblanc
Catherine
C
Lebret
Clemence
C
Schindler
Francis
F
Raza
Farheen
F
Walker
Christoph
C
Crosby
Alexi
A
Davies
Rachel J
RJ
Morrell
Nicholas W
NW
Budd
David C
DC
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
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