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Altered gene expression in pulmonary tissue of tryptophan hydroxylase-1 knockout mice: implications for pulmonary arterial hypertension

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Item Type:Article
Title:Altered gene expression in pulmonary tissue of tryptophan hydroxylase-1 knockout mice: implications for pulmonary arterial hypertension
Creators Name:Rothman, R.B. and Cadet, J.L. and Dersch, C.M. and McCoy, M.T. and Lehrmann, E. and Becker, K.G. and Bader, M. and Alenina, N. and Baumann, M.H.
Abstract:The use of fenfluramines can increase the risk of developing pulmonary arterial hypertension (PAH) in humans, but the mechanisms responsible are unresolved. A recent study reported that female mice lacking the gene for tryptophan hydroxylase-1 (Tph1(-/-) mice) were protected from PAH caused by chronic dexfenfluramine, suggesting a pivotal role for peripheral serotonin (5-HT) in the disease process. Here we tested two alternative hypotheses which might explain the lack of dexfenfluramine-induced PAH in Tph1(-/-) mice. We postulated that: 1) Tph1(-/-) mice express lower levels of pulmonary 5-HT transporter (SERT) when compared to wild-type controls, and 2) Tph1(-/-) mice display adaptive changes in the expression of non-serotonergic pulmonary genes which are implicated in PAH. SERT was measured using radioligand binding methods, whereas gene expression was measured using microarrays followed by quantitative real time PCR (qRT-PCR). Contrary to our first hypothesis, the number of pulmonary SERT sites was modestly up-regulated in female Tph1(-/-) mice. The expression of 51 distinct genes was significantly altered in the lungs of female Tph1(-/-) mice. Consistent with our second hypothesis, qRT-PCR confirmed that at least three genes implicated in the pathogenesis of PAH were markedly up-regulated: Has2, Hapln3 and Retlna. The finding that female Tph1(-/-) mice are protected from dexfenfluramine-induced PAH could be related to compensatory changes in pulmonary gene expression, in addition to reductions in peripheral 5-HT. These observations emphasize the intrinsic limitation of interpreting data from studies conducted in transgenic mice that are not fully characterized.
Keywords:Down-Regulation, Enzymologic Gene Expression Regulation, Pulmonary Hypertension, Lung, Oligonucleotide Array Sequence Analysis, Protein Binding, Reverse Transcriptase Polymerase Chain Reaction, Serotonin Plasma Membrane Transport Proteins, Tryptophan Hydroxylase, Up-Regulation, Animals, Mice
Source:PLoS ONE
Publisher:Public Library of Science
Page Range:e17735
Date:25 March 2011
Official Publication:https://doi.org/10.1371/journal.pone.0017735
PubMed:View item in PubMed

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