Effect of Tryptophan Hydroxylase 1 Deficiency on the Development of Hypoxia-Induced Pulmonary Hypertension

Abstract

Abstract-Tryptophan hydroxylase 1 catalyzes the rate-limiting step in the synthesis of serotonin in the periphery.Recently, it has been shown that expression of the tryptophan hydroxylase 1 gene is increased in lungs and pulmonary endothelial cells from patients with idiopathic pulmonary arterial hypertension. Here we investigated the effect of genetic deletion of tryptophan hydroxylase 1 on hypoxia-induced pulmonary arterial hypertension in mice by measuring pulmonary hemodynamics and pulmonary vascular remodeling before and after 2 weeks of hypoxia. In wild-type mice, hypoxia increased right ventricular pressure and pulmonary vascular remodeling. These effects of hypoxia were attenuated in the tryptophan hydroxylase 1 Ϫ/Ϫ mice. Hypoxia increased right ventricular hypertrophy in both wild-type and tryptophan hydroxylase 1 Ϫ/Ϫ mice suggesting that in vivo peripheral serotonin has a differential effect on the pulmonary vasculature and right ventricular hypertrophy. Contractile responses to serotonin were increased in pulmonary arteries from tryptophan hydroxylase 1 Ϫ/Ϫ mice. Hypoxia increased serotonin-mediated contraction in vessels from the wild-type mice, but this was not further increased by hypoxia in the tryptophan hydroxylase 1 Ϫ/Ϫ mice. In conclusion, these results indicate that tryptophan hydroxylase 1 and peripheral serotonin play an essential role in the development of hypoxia-induced elevations in pulmonary pressures and hypoxia-induced pulmonary vascular remodeling. In addition, the results suggest that, in mice, serotonin has differential effects on the pulmonary vasculature and right ventricular hypertrophy. Serotonin promotes pulmonary arterial smooth muscle cell proliferation, pulmonary arterial vasoconstriction, and local microthrombosis. 4 Proliferation of pulmonary arterial smooth muscle cells is an important component of pulmonary arterial remodeling in PAH, which accounts for the increased thickness of the medial muscular coat in normally muscularized arteries and extension of muscle into smaller and more peripheral arteries. Elevated circulating levels of peripheral serotonin have been associated with the development of PAH clinically. 5 It has also been shown that exogenously administered serotonin can potentiate the development of PAH in rats 6 and can uncover a PAH phenotype in bone morphogenetic protein receptor II ϩ/Ϫ mice. 7 Moreover, mice overexpressing SERT (SERTϩ mice) develop spontaneous PAH and are more susceptible to hypoxia-induced PAH, whereas mice deficient for the SERT are less susceptible. 8 -10 Blood serotonin levels are also elevated in mice after hypoxic exposure. 11 Tryptophan hydroxylase (Tph) catalyzes the rate-limiting step in the synthesis of serotonin from tryptophan. By studying Tph1 Ϫ/Ϫ

Serotonin 5-HT2B receptors are required for bone-marrow contribution to pulmonary arterial hypertension

“…Deletion of tryptophan hydroxylase 1 (the limiting enzyme in peripheral 5-HT synthesis), SERT, or 5-HT 1B Rs reduces pulmonary vascular remodeling and hypoxic pulmonary hypertension. 38 Locally, 5-HT has been shown to be a potent vasoconstrictor of isolated pulmonary arteries but also to stimulate pulmonary SMC proliferation. It has thus been implicated in various processes associated with pulmonary vascular remodeling.…”

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).…”

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).…”