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

Abstract

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 mgxkg(-1)xday(-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.

Why drugs fail in clinical trials in pulmonary arterial hypertension, and strategies to succeed in the future

“…5-HT is a pulmonary artery vasoconstrictor and induces proliferation of both pulmonary arterial fibroblasts and pulmonary arterial smooth muscle cells (Lee, Wang, Lanzillo, & Fanburg, 1994;MacLean, Herve, Eddahibi, & Adnot, 2000;Welsh, Harnett, MacLean, & Peacock, 2004). Inhibition of serotonin receptors, SERT and knockout of the rate-limiting enzyme producing 5-HT (tryptophan hydroxylase-1) have all been shown to inhibit development of PAH in animal models (Guignabert et al, 2005;Izikki et al, 2007;Keegan, Morecroft, Smillie, Hicks, & MacLean, 2001;Marcos et al, 2003;Morecroft et al, 2007).…”

Linoleic Acid Induces Calcium Signaling, Src Kinase Phosphorylation, and Neurotransmitter Release in Mouse CD36-positive Gustatory Cells

“…We have measured tryptophan hydroxylase-1 mRNA as the tph1 gene that encodes for the synthesis of tryptophan hydroxylase in peripheral tissues (13). Tryptophan hydroxylase-1 converts L-tryptophan to L-5-hydroxytryptophan.…”

Paracrine modulation of cholangiocyte serotonin synthesis orchestrates biliary remodeling in adults

“…TGF-␤ 1 inhibits Angpt1 (23), however, suggesting that this cytokine may regulate ductulogenesis by differentially influencing various stages of the process. In endothelial cells, Angpt1 activation of Tie2 induces tryptophan hydroxylase (TPH) and 5-hydroxytryptamine (5-HT, serotonin) production (4,5,10,35). It is not known whether 5-HT has any role in bile duct development during embryogenesis.…”