Inhibition of gut- and lung-derived serotonin attenuates pulmonary hypertension in mice. - Archive ouverte HAL Access content directly
Journal Articles American Journal of Physiology - Lung Cellular and Molecular Physiology Year : 2012

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

(1) , (1) , (2) , (1) , (1) , (1) , (1) , (1) , (1) , (1, 3) , (2) , (1)
1
2
3

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.
Embargoed file
Embargoed file
Ne sera jamais visible
Loading...

Dates and versions

inserm-00747026 , version 1 (30-10-2012)

Identifiers

Cite

Shariq Abid, Amal Houssaini, Caroline Chevarin, Elisabeth Marcos, Claire-Marie Tissot, et al.. Inhibition of gut- and lung-derived serotonin attenuates pulmonary hypertension in mice.. American Journal of Physiology - Lung Cellular and Molecular Physiology, 2012, 303 (6), pp.L500-8. ⟨10.1152/ajplung.00049.2012⟩. ⟨inserm-00747026⟩
131 View
0 Download

Altmetric

Share

Gmail Facebook Twitter LinkedIn More