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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., Cadet, J.L., Dersch, C.M., McCoy, M.T., Lehrmann, E., Becker, K.G., Bader, M., 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 |
| ISSN: | 1932-6203 |
| Publisher: | Public Library of Science |
| Volume: | 6 |
| Number: | 3 |
| 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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