Imatinib Attenuates Hypoxia-Induced PAH Pathology Via Reduction In Serotonin Through Inhibition Of Tryptophan Hydroxylase 1 Expression

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

doi:10.1164/ajrccm-conference.2012.185.1_meetingabstracts.a1242

Cited by 5 publications

(6 citation statements)

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“…Serotonin has been implicated in the PH observed in the SERT 1 mouse (38), hypoxic rodents (38)(39)(40), the sugen/hypoxic rodent (41), and dexfenfluramine-treated female mice (18). In these models, estrogen plays a causative role in the development of PH.…”

Section: Discussionmentioning

confidence: 99%

Sex Affects Bone Morphogenetic Protein Type II Receptor Signaling in Pulmonary Artery Smooth Muscle Cells

Mair

Lü

et al. 2015

Am J Respir Crit Care Med

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Rationale: Major pulmonary arterial hypertension (PAH) registries report a greater incidence of PAH in women; mutations in the bone morphogenic protein type II receptor (BMPR-II) occur in approximately 80% of patients with heritable PAH (hPAH).Objectives: We addressed the hypothesis that women may be predisposed to PAH due to normally reduced basal BMPR-II signaling in human pulmonary artery smooth muscle cells (hPASMCs). Methods:We examined the BMPR-II signaling pathway in hPASMCs derived from men and women with no underlying cardiovascular disease (non-PAH hPASMCs). We also determined the development of pulmonary hypertension in male and female mice deficient in Smad1.Measurements and Main Results: Platelet-derived growth factor, estrogen, and serotonin induced proliferation only in non-PAH female hPASMCs. Female non-PAH hPASMCs exhibited reduced messenger RNA and protein expression of BMPR-II, the signaling intermediary Smad1, and the downstream genes, inhibitors of DNA binding proteins, Id1 and Id3. Induction of phospho-Smad1/5/8 and Id protein by BMP4 was also reduced in female hPASMCs. BMP4 induced proliferation in female, but not male, hPASMCs. However, small interfering RNA silencing of Smad1 invoked proliferative responses to BMP4 in male hPASMCs. In male hPASMCs, estrogen decreased messenger RNA and protein expression of Id genes. The estrogen metabolite 4-hydroxyestradiol decreased phosphoSmad1/5/8 and Id expression in female hPASMCs while increasing these in males commensurate with a decreased proliferative effect in male hPASMCs. Female Smad1 1/2 mice developed pulmonary hypertension (reversed by ovariectomy). Conclusions:We conclude that estrogen-driven suppression of BMPR-II signaling in non-PAH hPASMCs derived from women contributes to a pro-proliferative phenotype in hPASMCs that may predispose women to PAH.

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Section: Discussionmentioning

confidence: 99%

Sex Affects Bone Morphogenetic Protein Type II Receptor Signaling in Pulmonary Artery Smooth Muscle Cells

Mair

Lü

et al. 2015

Am J Respir Crit Care Med

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“…Indeed, a hypoxia-dependent TPH1 expression has been showed diminished by administration of PDGFR antagonist. [37] Those new data deepen our knowledge concerning the action of PDGF inhibitors.…”

Section: Growth Factorsmentioning

confidence: 95%

Signal Transduction in the Development of Pulmonary Arterial Hypertension

et al. 2013

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Pulmonary arterial hypertension (PAH) is a unique disease. Properly speaking, it is not a disease of the lung. It can be seen more as a microvascular disease occurring mainly in the lungs and affecting the heart. At the cellular level, the PAH paradigm is characterized by inflammation, vascular tone imbalance, pulmonary arterial smooth muscle cell proliferation and resistance to apoptosis and the presence of in situ thrombosis. At a clinical level, the aforementioned abnormal vascular properties alter physically the pulmonary circulation and ventilation, which greatly influence the right ventricle function as it highly correlates with disease severity. Consequently, right heart failure remains the principal cause of death within this cohort of patients. While current treatment modestly improve patients’ conditions, none of them are curative and, as of today, new therapies are lacking. However, the future holds potential new therapies that might have positive influence on the quality of life of the patient. This article will first review the clinical presentation of the disease and the different molecular pathways implicated in the pathobiology of PAH. The second part will review tomorrow's future putative therapies for PAH.

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“…This study suggested that imatinib may downregulate TPH1 via inhibition of PDGFβ signaling. 29 To date, drug design for TPH1 selectivity has been dependent on developing unselective TPH inhibitors that do not cross the blood–brain barrier. 87 However, biochemical and biophysical characterization of a novel allosteric site on TPH1 through which selectivity over TPH2 and related aromatic amino acid hydroxylases can be achieved has recently been described.…”

Section: Tph1mentioning

confidence: 99%

“…9,11 There is growing evidence that genetic ablation of TPH1 or pharmacological inhibition can protect against or reverse experimental PH including in the hypoxic, monocrotaline, dexfenfluramine, and sugen/hypoxic animal models. 11,29,74,[83][84][85][86] This has led to recent interest in the use of TPH1 inhibitors for the treatment of PAH patients. Post hoc subgroup analysis has suggested that PAH patients with greater hemodynamic impairment had reduced serotonin plasma levels following imatinib treatment, compared with placebo.…”

Section: Tph1mentioning

confidence: 99%

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The serotonin hypothesis in pulmonary hypertension revisited: targets for novel therapies (2017 Grover Conference Series)

MacLean

2018

Pulm. circ.

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Increased synthesis of serotonin and/or activity of serotonin in pulmonary arteries has been implicated in the pathobiology of pulmonary arterial hypertension (PAH). The incidence of PAH associated with diet pills such as aminorex, fenfluramine, and chlorphentermine initially led to the “serotonin hypothesis of pulmonary hypertension.” Over the last couple of decades there has been an accumulation of convincing evidence that targeting serotonin synthesis or signaling is a novel and promising approach to the development of novel therapies for PAH. Pulmonary endothelial serotonin synthesis via tryptophan hydroxlase 1 (TPH1) is increased in patients with PAH and serotonin can act in a paracrine fashion on underlying pulmonary arterial smooth muscle cells (PASMCs), In humans, serotonin can enter PASMCs via the serotonin transporter (SERT) or activate the 5-HT1B receptor; 5-HT1B activation and SERT activity cooperate to induce PASMC contraction and proliferation via activation of downstream proliferative and contractile signaling pathways. Here we will review the current status of the serotonin hypothesis and discuss potential and novel therapeutic targets.

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Imatinib Attenuates Hypoxia-Induced PAH Pathology Via Reduction In Serotonin Through Inhibition Of Tryptophan Hydroxylase 1 Expression

Cited by 5 publications

References 0 publications

Sex Affects Bone Morphogenetic Protein Type II Receptor Signaling in Pulmonary Artery Smooth Muscle Cells

Sex Affects Bone Morphogenetic Protein Type II Receptor Signaling in Pulmonary Artery Smooth Muscle Cells

Signal Transduction in the Development of Pulmonary Arterial Hypertension

The serotonin hypothesis in pulmonary hypertension revisited: targets for novel therapies (2017 Grover Conference Series)

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