Inhibition of gut- and lung-derived serotonin attenuates pulmonary hypertension in mice

Abstract

Decreasing the bioavailability of serotonin (5-HT) by inhibiting its biosynthesis may represent a useful adjunctive treatment of pulmonary hypertension (PH). We assessed this hypothesis using LP533401, which inhibits the rate-limiting enzyme tryptophan hydroxylase 1 (Tph1) expressed in the gut and lung, without inhibiting Tph2 expressed in neurons. Mice treated repeatedly with LP533401 (30-250 mg/kg per day) exhibited marked 5-HT content reductions in the gut, lungs, and blood, but not in the brain. After a single LP533401 dose (250 mg/kg), lung and gut 5-HT contents decreased by 50%, whereas blood 5-HT levels remained unchanged, suggesting gut and lung 5-HT synthesis. Treatment with the 5-HT transporter (5-HTT) inhibitor citalopram decreased 5-HT contents in the blood and lungs but not in the gut. In transgenic SM22-5-HTT+ mice, which overexpress 5-HTT in smooth muscle cells and spontaneously develop PH, 250 mg/kg per day LP533401 or 10 mg/kg per day citalopram for 21 days markedly reduced lung and blood 5-HT levels, right ventricular (RV) systolic pressure, RV hypertrophy, distal pulmonary artery muscularization, and vascular Ki67-positive cells (P < 0.001). Combined treatment with both drugs was more effective in improving PH-related hemodynamic parameters than either drug alone. LP533401 or citalopram treatment partially prevented PH development in wild-type mice exposed to chronic hypoxia. Lung and blood 5-HT levels were lower in hypoxic than in normoxic mice and decreased further after LP533401 or citalopram treatment. These results provide proof of concept that inhibiting Tph1 may represent a new therapeutic strategy for human PH.

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

“…However, the hypothesized inhibition of lung TPH1 by LP533401 was based on lung measures containing 5-HT-devoid platelets. In addition, the surprising lack of pathway activation within the chronic hypoxia model used questions the validity of serotonin pathway involvement / analytics (Abid et al, 2012). …”

Serotonin: a novel bone mass controller may have implications for alveolar bone

“…The serotoninergic transmission has a broad spectrum of effects and has been associated to neural development [6], numerous behavioral and mood disorders [7-11] and to central modulation of pain [12]. Serotonin, however, can also be synthesized by heterochromaffin cells in the gut, where it regulates gastrointestinal function [13], by endothelial cells in the lung [14] and can be found sequestered inside platelet granules [15,16]. As serotonin cannot cross the hematoencephalic barrier, it forms two physically and functionally separated pools, the former inside the central nervous system and the latter in the peripheral body.…”

A Sex-Specific MicroRNA-96/5-Hydroxytryptamine 1B Axis Influences Development of Pulmonary Hypertension

“…In addition, TPH-1 knockout mice are protected from hypoxia-induced pulmonary hypertension (PH) (10,11). We have shown that only female mice develop PH via a serotonin-dependent mechanism-for example, mice overexpressing the serotonin transporter (SERT), calcium-binding protein S100A4/mts1-overexpressing mice, and mice dosed with dexfenfluramine (6,12,13).…”