Tryptophan hydroxylase 1 knockout and tryptophan hydroxylase 2 polymorphism: effects on hypoxic pulmonary hypertension in mice

1 Institut National de la Santé et de la Recherche Médicale U841 and Département de Physiologie, Hôpital H. Mondor, Assistance Publique-Hôpitaux de Paris, Créteil; and 2 Unité Mixte de Recherche 677 Institut National de la Santé et de la Recherche Médicale/Université Pierre et Marie Curie, NeuroPsychoPharmacologie, Faculté de Médecine Pitié-Salpêtrière, Paris Cedex, France Submitted 5 March 2007 ; accepted in final form 20 July 2007 Serotonin [5-hydroxytryptamine (5-HT)] biosynthesis depends on two rate-limiting tryptophan hydroxylases (Tph): Tph1, which is expressed in peripheral organs, and Tph2, which is expressed in neurons. Because 5-HT is involved in pulmonary hypertension (PH), we investigated whether genetic variations in Tph1 and/or Tph2 affected PH development in mice. To examine the functional impact of peripheral Tph1 deficiency on hypoxic PH, we used Tph1 –/– mice characterized by very low 5-HT synthesis rates and contents in the gut and lung and increased 5-HT synthesis in the forebrain. With chronic hypoxia, 5-HT synthesis in the forebrain increased further. Hypoxic PH, right ventricular hypertrophy, and distal pulmonary artery muscularization were less severe ( P < 0.001) than in wild-type controls. The Tph inhibitor p -chlorophenylalanine (100 mg·kg –1 ·day –1 ) further improved these parameters. We then investigated whether mouse strains harboring the C1473G polymorphism of the Tph2 gene showed different PH phenotypes during hypoxia. Forebrain Tph activity was greater and hypoxic PH was more severe in C57Bl/6 and 129X1/SvJ mice homozygous for the 1473C allele than in DBA/2 and BALB/cJ mice homozygous for the 1473G allele. p -Chlorophenylalanine reduced PH in all groups and abolished the difference in PH severity across mouse strains. Hypoxia increased 5-hydroxytryptophan accumulation but decreased 5-HT contents in the forebrain and lung, suggesting accelerated 5-HT turnover during hypoxia. These results provide evidence that dysregulation of 5-HT synthesis is closely linked to the hypoxic PH phenotype in mice and that Tph1 and Tph2 may contribute to PH development. vascular smooth muscle; transgenic mice Address for reprint requests and other correspondence: S. Adnot, INSERM U841, Faculté de Médecine, 94010, Créteil, France (e-mail: serge.adnot{at}creteil.inserm.fr )