Imatinib attenuates hypoxia-induced pulmonary arterial hypertension pathology via reduction in 5-hydroxytryptamine through inhibition of tryptophan hydroxylase 1 expression

Loredana Ciuclan, Martin J. Hussey, Victoria Burton, Robert Good, Nicholas Duggan, Sarah Beach, Peter Jones, Roy Fox, Ieuan Clay, Olivier Bonneau, Irena Konstantinova, Andrew Pearce, David J. Rowlands, Gabor Jarai, John Westwick, Margaret R. MacLean, Matthew Thomas

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

Rationale: 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. Objectives: 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. Measurements and Main 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 controlgroup. 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 inpulmonary 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.

Original languageEnglish
Pages (from-to)78-89
Number of pages12
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume187
Issue number1
DOIs
Publication statusPublished - 1 Jan 2013

Keywords

  • 5-Hydroxytryptamine
  • animal preclinical models
  • imatinib
  • platelet-derived growth factor receptor
  • pulmonary arterial hypertension

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