title: Imatinib attenuates hypoxia-induced pulmonary arterial hypertension pathology via reduction in 5-hydroxytryptamine through inhibition of tryptophan hydroxylase 1 expression.
abstract: BACKGROUND
  Whether idiopathic, familial, or secondary to another disease, pulmonary arterial hypertension (PAH) is characterized by increased vascular tone, neointimal hyperplasia, medial hypertrophy, and adventitial fibrosis. Imatinib, a potent receptor tyrosine kinase inhibitor, reverses pulmonary remodeling in animal models of PAH and improves hemodynamics and exercise capacity in selected patients with PAH.
  
  
  OBJECTIVE
  Here we use both imatinib and knockout animals to determine the relationship between platelet-derived growth factor receptor (PDGFR) and serotonin signaling and investigate the PAH pathologies each mediates.
  
  
  METHODS
  We investigated the effects of imatinib (100 mg/kg) on hemodynamics, vascular remodeling, and downstream molecular signatures in the chronic hypoxia/SU5416 murine model of PAH.
  
  
  RESULTS
  Treatment with imatinib reduced all measures of PAH pathology observed in hypoxia/SU5416 mice. In addition, 5-hydroxytryptamine (5-HT) and tryptophan hydroxylase 1 (Tph1) expression were reduced compared with the normoxia/SU5416 control group. Imatinib attenuated hypoxia-induced increases in Tph1 expression in pulmonary endothelial cells in vitro via inhibition of the PDGFR-β pathway. To better understand the consequences of this novel mode of action for imatinib, we examined the development of PAH after hypoxic/SU5416 exposure in Tph1-deficient mice (Tph1(-/-)). The extensive changes in pulmonary vascular remodeling and hemodynamics in response to hypoxia/SU5416 were attenuated in Tph1(-/-) mice and further decreased after imatinib treatment. However, imatinib did not significantly further impact collagen deposition and collagen 3a1 expression in hypoxic Tph1(-/-) mice. Post hoc subgroup analysis suggests that patients with PAH with greater hemodynamic impairment showed significantly reduced 5-HT plasma levels after imatinib treatment compared with placebo.
  
  
  CONCLUSIONS
  We report a novel mode of action for imatinib, demonstrating TPH1 down-regulation via inhibition of PDGFR-β signaling. Our data reveal interplay between PDGF and 5-HT pathways within PAH, demonstrating TPH1-dependent imatinib efficacy in collagen-mediated mechanisms of fibrosis.
authors.affiliation: Respiratory Disease Area, Novartis Institutes for BioMedical Research, Horsham, West Sussex, UK.
authors.forename: Loredana
authors.initials: L
authors.lastname: Ciuclan
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Hussey
authors.forename: Victoria
authors.initials: V
authors.lastname: Burton
authors.forename: Robert
authors.initials: R
authors.lastname: Good
authors.forename: Nicholas
authors.initials: N
authors.lastname: Duggan
authors.forename: Sarah
authors.initials: S
authors.lastname: Beach
authors.forename: Peter
authors.initials: P
authors.lastname: Jones
authors.forename: Roy
authors.initials: R
authors.lastname: Fox
authors.forename: Ieuan
authors.initials: I
authors.lastname: Clay
authors.forename: Olivier
authors.initials: O
authors.lastname: Bonneau
authors.forename: Irena
authors.initials: I
authors.lastname: Konstantinova
authors.forename: Andrew
authors.initials: A
authors.lastname: Pearce
authors.forename: David J
authors.initials: DJ
authors.lastname: Rowlands
authors.forename: Gabor
authors.initials: G
authors.lastname: Jarai
authors.forename: John
authors.initials: J
authors.lastname: Westwick
authors.forename: Margaret R
authors.initials: MR
authors.lastname: MacLean
authors.forename: Matthew
authors.initials: M
authors.lastname: Thomas
mesh_terms: D000818:Animals; D001549:Benzamides; D004195:Disease Models, Animal; D006439:Hemodynamics / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D000860:Hypoxia / Q000150:complications; D000068877:Imatinib Mesylate; D007211:Indoles / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D014365:Tryptophan Hydroxylase / Q000378:metabolism*
chemical_list: D001549:Benzamides; D007211:Indoles; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D012701:Serotonin; C116890:Semaxinib; D000068877:Imatinib Mesylate; C487801:Tph1 protein, mouse; D014365:Tryptophan Hydroxylase; D011505:Protein-Tyrosine Kinases; D020797:Receptor, Platelet-Derived Growth Factor beta