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
<b>Rationale:</b> 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. <p></p> <b>Objectives:</b> 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. <p></p> <b>Methods:</b> 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. <p></p> <b>Measurements and Main Results:</b> 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. <p></p> <b>Conclusions:</b> 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. <p></p>
| 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 > School of Cardiovascular & Metabolic Health |
| 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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