Imatinib Attenuates Hypoxia-induced Pulmonary Arterial Hypertension Pathology via Reduction in 5-Hydroxytryptamine through Inhibition of Tryptophan Hydroxylase 1 Expression

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

doi:10.1164/rccm.201206-1028oc

Cited by 58 publications

(48 citation statements)

References 51 publications

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“…Improvements in these areas would provide a tool by which more direct assessment of efficacy upon 5-HT-mediated complex remodeling diseases of the periphery could be made – an example of which could be the rodent hypoxia/SUGEN model of PAH which demonstrates increased TPH1 expression and 5-HT production, and is also sensitive to pCPA inhibition (Ciuclan et al, 2013; Thomas et al, 2013). Increased pulmonary artery endothelial cell (PAEC) TPH1 expression in PAH patients together with increased SERT expression in pulmonary artery smooth muscle cells (PASMC), may induce the hyperplasia central to PAH (Eddahibi et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Identification of a Novel Allosteric Inhibitory Site on Tryptophan Hydroxylase 1 Enabling Unprecedented Selectivity Over all Related Hydroxylases

Petrassi

Barber

et al. 2017

Front. Pharmacol.

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Pulmonary arterial hypertension (PAH) has demonstrated multi-serotonin receptor dependent pathologies, characterized by increased tone (5-HT1B receptor) and complex lesions (SERT, 5-HT1B, 5-HT2B receptors) of the pulmonary vasculature together with right ventricular hypertrophy, ischemia and fibrosis (5-HT2B receptor). Selective inhibitors of individual signaling elements – SERT, 5-HT2A, 5HT2B, and combined 5-HT2A/B receptors, have all been tested clinically and failed. Thus, inhibition of tryptophan hydroxylase 1 (TPH1), the rate limiting step in 5-HT synthesis, has been suggested as a more broad, and thereby more effective, mode of 5-HT inhibition. However, selectivity over non-pathogenic enzyme family members, TPH2, phenylalanine hydroxylase, and tyrosine hydroxylase has hampered therapeutic development. Here we describe the site/sequence, biochemical, and biophysical characterization of a novel allosteric site on TPH1 through which selectivity over TPH2 and related aromatic amino acid hydroxylases is achieved. We demonstrate the mechanism of action by which novel compounds selectively inhibit TPH1 using surface plasma resonance and enzyme competition assays with both tryptophan ligand and BH4 co-factor. We demonstrate 15-fold greater potency within a human carcinoid cell line versus the most potent known TPH1/2 non-specific inhibitor. Lastly, we detail a novel canine in vivo system utilized to determine effective biologic inhibition of newly synthesized 5-HT. These findings are the first to demonstrate TPH1-selective inhibition and may pave the way to a truly effective means to reduce pathologic 5-HT and thereby treat complex remodeling diseases such as PAH.

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Section: Discussionmentioning

confidence: 99%

Identification of a Novel Allosteric Inhibitory Site on Tryptophan Hydroxylase 1 Enabling Unprecedented Selectivity Over all Related Hydroxylases

Petrassi

Barber

et al. 2017

Front. Pharmacol.

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“…As a novel approach to PAH, PDGF inhibitors have received attention (4,10,23). However, toxicities of PDGF inhibitors and heterogeneous actions of the agents are obstacles in their translation to clinical use.…”

Section: Discussionmentioning

confidence: 99%

“…However, the prognosis of PAH still remains poor (9,31). Several recent studies using animal models of PAH have indicated that proliferation of vascular cells and their escape from apoptosis are therapeutic targets, and that inhibition of the platelet-derived growth factor (PDGF) receptor may prevent and reverse PAH (4,11,23). However, current inhibitors of growth factor receptors are, in general, not highly specific and have different efficacies and serious side effects, which make the inhibitors unsuitable for clinical application.…”

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confidence: 99%

Reduction of endoplasmic reticulum stress by 4-phenylbutyric acid prevents the development of hypoxia-induced pulmonary arterial hypertension

Koyama

Furuhashi

Ishimura

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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Koyama M, Furuhashi M, Ishimura S, Mita T, Fuseya T, Okazaki Y, Yoshida H, Tsuchihashi K, Miura T. Reduction of endoplasmic reticulum stress by 4-phenylbutyric acid prevents the development of hypoxia-induced pulmonary arterial hypertension. Am J Physiol Heart Circ Physiol 306: H1314 -H1323, 2014. First published March 7, 2014 doi:10.1152/ajpheart.00869.2013.-Pulmonary arterial hypertension (PAH) is characterized by vasoconstriction and vascular remodeling of the pulmonary artery (PA). Recently, endoplasmic reticulum (ER) stress and inappropriate adaptation through the unfolded protein response (UPR) have been disclosed in various types of diseases. Here we examined whether ER stress is involved in the pathogenesis of PAH. Four weeks of chronic normobaric hypoxia increased right ventricular (RV) systolic pressure by 63% compared with that in normoxic controls and induced RV hypertrophy and medial thickening of the PA in C57BL/6J mice. Treatment with 4-phenylbutyric acid (4-PBA), a chemical chaperone, significantly reduced RV systolic pressure by 30%, attenuated RV hypertrophy and PA muscularization, and increased total running distance in a treadmill test by 70% in hypoxic mice. The beneficial effects of 4-PBA were associated with suppressed expression of inflammatory cytokines and ER stress markers, including Grp78 and Grp94 in the activating transcription factor-6 branch, sXbp1 and Pdi in the inositolrequiring enzyme-1 branch and Atf4 in the PKR-like ER kinase branch, and reduced phosphorylation of c-Jun NH 2-terminal kinase and eukaryotic translation initiation factor-2␣ in the lung. The pattern of changes in ER stress and inflammatory markers by 4-PBA in the lung of the PAH model was reproduced in PA smooth muscle cells by chronic stimulation of platelet-derived growth factor-BB or hypoxia. Furthermore, knockdown of each UPR branch sensor activated other branches and promoted proliferation of PA smooth muscle cells. The findings indicate that activation of all branches of the UPR and accompanying inflammation play a major role in the pathogenesis of PAH, and that chemical chaperones are potentially therapeutic agents for PAH. endoplasmic reticulum stress; chemical chaperone; pulmonary arterial hypertension; vascular smooth muscle cell; platelet-derived growth factor; inflammation PULMONARY ARTERIAL HYPERTENSION (PAH) is characterized by vasoconstriction, micro-thrombosis, and vascular remodeling in the pulmonary vasculature and progresses insidiously with dismal outcomes (26). The pathogenesis of PAH is not fully understood, but growth factor receptors, protease-activated receptor-2, increased elastase activity, dysfunction of ion channels (voltage-dependent K ϩ and transient receptor potential channels), loss of adenomatous polyposis coli-␣3 integrin interaction, and inflammatory cytokines have been suggested to be involved in proliferation of vascular cells in the lung (2,5,15,24). Vasodilatory agents, including prostanoids, endothelin receptor antagonists, and phosphodiesterase type-5 (PDE5) inhibitors, h...

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“…1,20 Wu et al 21 examined PDGFR signaling in genetically defined mouse embryonic fibroblasts (MEFs). The MEFs were engineered to express only PDGFRα or PDGFRβ, both, or neither.…”

Section: Discussionmentioning

confidence: 99%

PK10453, a Nonselective Platelet‐Derived Growth Factor Receptor Inhibitor, Prevents the Progression of Pulmonary Arterial Hypertension

et al. 2014

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The platelet-derived growth factor (PDGF) signaling pathway has been found to be activated in human pulmonary arterial hypertension (PAH) and in animal models of the disease. Our study tested the hypothesis that a novel, nonselective inhaled PDGF receptor inhibitor, PK10453, would decrease pulmonary hypertension both in the rat monocrotaline (MCT) model and the rat MCT plus pneumonectomy (MCT+PN) model of PAH. PK10453, delivered by inhalation for 4 (D4)-and 8 (D8)-minute exposures 3 times a day for 2 weeks, decreased right ventricular systolic pressure (RVSP) in both the rat MCT and rat MCT+PN models: RVSP was 80.4 AE 2.6 mmHg in the vehicle MCT group (n ¼ 6), 44.4 AE 5.8 mmHg in the D4 MCT group (n ¼ 6), and 37.1 AE 4.5 mmHg in the D8 MCT group (n ¼ 5; P < 0.001 vs. vehicle); RVSP was 75.7 AE 7.1 mmHg in the vehicle MCT+PN group (n ¼ 9), 40.4 AE 2.7 mmHg in the D4 MCT+PN group (n ¼ 10), and 43.0 AE 3.0 mmHg in the D8 MCT+PN group (n ¼ 8; P < 0.001). In the rat MCT+PN model, continuous telemetry monitoring of pulmonary artery pressures also demonstrated that PK10453 prevented the progression of PAH. Imatinib given by inhalation was equally effective in the MCT model but was not effective in the MCT+PN model. Immunohistochemistry demonstrated increased activation of the PDGFβ receptor compared to the PDGFα receptor in neointimal and perivascular lesions found in the MCT+PN model. We show that imatinib is selective for the PDGFα receptor, whereas PK10453 has a lower half-maximal inhibitor concentration (IC50) for inhibition of kinase activity of both the PDGFα and PDGFβ receptors compared to imatinib. In conclusion, PK10453, when delivered by inhalation, significantly decreased the progression of PAH in the rat MCT and MCT+PN models. Nonselective inhibition of both the PDGFα and PDGFβ receptors may have a therapeutic advantage over selective PDGFα receptor inhibition in PAH.

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Imatinib Attenuates Hypoxia-induced Pulmonary Arterial Hypertension Pathology via Reduction in 5-Hydroxytryptamine through Inhibition of Tryptophan Hydroxylase 1 Expression

Abstract: 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.

Cited by 58 publications

References 51 publications

Identification of a Novel Allosteric Inhibitory Site on Tryptophan Hydroxylase 1 Enabling Unprecedented Selectivity Over all Related Hydroxylases

Identification of a Novel Allosteric Inhibitory Site on Tryptophan Hydroxylase 1 Enabling Unprecedented Selectivity Over all Related Hydroxylases

Reduction of endoplasmic reticulum stress by 4-phenylbutyric acid prevents the development of hypoxia-induced pulmonary arterial hypertension

PK10453, a Nonselective Platelet‐Derived Growth Factor Receptor Inhibitor, Prevents the Progression of Pulmonary Arterial Hypertension

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