Inhibition of gut- and lung-derived serotonin attenuates pulmonary hypertension in mice.
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.
INSERM U955 Team 8 and Département de Physiologie, Hôpital Henri Mondor, AP-HP, Créteil. shariqraj@hotmail.com
Shariq
S
Abid
Amal
A
Houssaini
Caroline
C
Chevarin
Elisabeth
E
Marcos
Claire-Marie
CM
Tissot
Guillaume
G
Gary-Bobo
Feng
F
Wan
Nathalie
N
Mouraret
Valerie
V
Amsellem
Jean-Luc
JL
Dubois-Randé
Michel
M
Hamon
Serge
S
Adnot
D000818:Animals; D015283:Citalopram / Q000494:pharmacology*; D004386:Duodenum / Q000187:drug effects / Q000378:metabolism*; D006976:Hypertension, Pulmonary / Q000517:prevention & control*; D000860:Hypoxia / Q000503:physiopathology; D008168:Lung / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D011743:Pyrimidines / Q000494:pharmacology*; D012701:Serotonin / Q000096:biosynthesis / Q000097:blood / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000096:biosynthesis; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D014365:Tryptophan Hydroxylase / Q000037:antagonists & inhibitors
D015283:Citalopram; D011743:Pyrimidines; D012701:Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D014365:Tryptophan Hydroxylase; C548240:LP533401; C487801:Tph1 protein, mouse