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

37 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.

LanguageEnglish
Pages78-89
Number of pages12
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume187
Issue number1
DOIs
Publication statusPublished - 1 Jan 2013

Fingerprint

Tryptophan Hydroxylase
Pulmonary Hypertension
Serotonin
Pathology
Hemodynamics
Platelet-Derived Growth Factor beta Receptor
Collagen
Fibrosis
Imatinib Mesylate
Hypoxia
Platelet-Derived Growth Factor Receptors
Adventitia
Lung
Receptor Protein-Tyrosine Kinases
Hypertrophy
Hyperplasia
Blood Vessels
Therapeutics
Down-Regulation
Endothelial Cells

Keywords

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

Cite this

Ciuclan, Loredana ; Hussey, Martin J. ; Burton, Victoria ; Good, Robert ; Duggan, Nicholas ; Beach, Sarah ; Jones, Peter ; Fox, Roy ; Clay, Ieuan ; Bonneau, Olivier ; Konstantinova, Irena ; Pearce, Andrew ; Rowlands, David J. ; Jarai, Gabor ; Westwick, John ; MacLean, Margaret R. ; Thomas, Matthew. / Imatinib attenuates hypoxia-induced pulmonary arterial hypertension pathology via reduction in 5-hydroxytryptamine through inhibition of tryptophan hydroxylase 1 expression. In: American Journal of Respiratory and Critical Care Medicine. 2013 ; Vol. 187, No. 1. pp. 78-89.
@article{1661604e669c4ab5aed380c15f00e73f,
title = "Imatinib attenuates hypoxia-induced pulmonary arterial hypertension pathology via reduction in 5-hydroxytryptamine through inhibition of tryptophan hydroxylase 1 expression",
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.",
keywords = "5-Hydroxytryptamine, animal preclinical models, imatinib, platelet-derived growth factor receptor, pulmonary arterial hypertension",
author = "Loredana Ciuclan and Hussey, {Martin J.} and Victoria Burton and Robert Good and Nicholas Duggan and Sarah Beach and Peter Jones and Roy Fox and Ieuan Clay and Olivier Bonneau and Irena Konstantinova and Andrew Pearce and Rowlands, {David J.} and Gabor Jarai and John Westwick and MacLean, {Margaret R.} and Matthew Thomas",
year = "2013",
month = "1",
day = "1",
doi = "10.1164/rccm.201206-1028OC",
language = "English",
volume = "187",
pages = "78--89",
journal = "American Journal of Respiratory and Critical Care Medicine",
issn = "1073-449X",
number = "1",

}

Ciuclan, L, Hussey, MJ, Burton, V, Good, R, Duggan, N, Beach, S, Jones, P, Fox, R, Clay, I, Bonneau, O, Konstantinova, I, Pearce, A, Rowlands, DJ, Jarai, G, Westwick, J, MacLean, MR & Thomas, M 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, vol. 187, no. 1, pp. 78-89. https://doi.org/10.1164/rccm.201206-1028OC

Imatinib attenuates hypoxia-induced pulmonary arterial hypertension pathology via reduction in 5-hydroxytryptamine through inhibition of tryptophan hydroxylase 1 expression. / Ciuclan, Loredana; Hussey, Martin J.; Burton, Victoria; Good, Robert; Duggan, Nicholas; Beach, Sarah; Jones, Peter; Fox, Roy; Clay, Ieuan; Bonneau, Olivier; Konstantinova, Irena; Pearce, Andrew; Rowlands, David J.; Jarai, Gabor; Westwick, John; MacLean, Margaret R.; Thomas, Matthew.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 187, No. 1, 01.01.2013, p. 78-89.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Imatinib attenuates hypoxia-induced pulmonary arterial hypertension pathology via reduction in 5-hydroxytryptamine through inhibition of tryptophan hydroxylase 1 expression

AU - Ciuclan, Loredana

AU - Hussey, Martin J.

AU - Burton, Victoria

AU - Good, Robert

AU - Duggan, Nicholas

AU - Beach, Sarah

AU - Jones, Peter

AU - Fox, Roy

AU - Clay, Ieuan

AU - Bonneau, Olivier

AU - Konstantinova, Irena

AU - Pearce, Andrew

AU - Rowlands, David J.

AU - Jarai, Gabor

AU - Westwick, John

AU - MacLean, Margaret R.

AU - Thomas, Matthew

PY - 2013/1/1

Y1 - 2013/1/1

N2 - 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.

AB - 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.

KW - 5-Hydroxytryptamine

KW - animal preclinical models

KW - imatinib

KW - platelet-derived growth factor receptor

KW - pulmonary arterial hypertension

UR - http://www.scopus.com/inward/record.url?scp=84871985829&partnerID=8YFLogxK

UR - https://www.atsjournals.org/journal/ajrccm

U2 - 10.1164/rccm.201206-1028OC

DO - 10.1164/rccm.201206-1028OC

M3 - Article

VL - 187

SP - 78

EP - 89

JO - American Journal of Respiratory and Critical Care Medicine

T2 - American Journal of Respiratory and Critical Care Medicine

JF - American Journal of Respiratory and Critical Care Medicine

SN - 1073-449X

IS - 1

ER -