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

Ciuclan, L. et al. (2013) Imatinib attenuates hypoxia-induced pulmonary arterial hypertension pathology via reduction in 5-hydroxytryptamine through inhibition of tryptophan hydroxylase 1 expression. American Journal of Respiratory and Critical Care Medicine, 187(1), pp. 78-89. (doi:10.1164/rccm.201206-1028OC)

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Publisher's URL: http://dx.doi.org/10.1164/rccm.201206-1028OC

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 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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:MacLean, Professor Margaret
Authors: Ciuclan, L., Hussey, M. J., Burton, V., Good, R., Duggan, N., Beach, S., Jones, P., Fox, R., Clay, I., Bonneau, O., Konstantinova, I., Pearce, A., Rowlands, D. J., Jarai, G., Westwick, J., MacLean, M. R., and Thomas, M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:American Journal of Respiratory and Critical Care Medicine
Publisher:American Thoracic Society
ISSN:1073-449X
ISSN (Online):1535-4970
Published Online:18 October 2012
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
536791Effect of oestrogens and oestrogen metabolites on the serotonin system: role in the development of pulmonary hypertensionMargaret MacleanBritish Heart Foundation (BHF)FS/10/019/28205RI CARDIOVASCULAR & MEDICAL SCIENCES
573731Gender and the development of pulmonary arterial hypertension: regulation of genes from mouse to manMargaret MacleanBritish Heart Foundation (BHF)RG/11/7/28916RI CARDIOVASCULAR & MEDICAL SCIENCES
573733Gender and the development of pulmonary arterial hypertension: regulation of genes from mouse to manMargaret MacleanBritish Heart Foundation (BHF)RG/11/7/28916RI CARDIOVASCULAR & MEDICAL SCIENCES