Title |
Altered Gene Expression in Pulmonary Tissue of Tryptophan Hydroxylase-1 Knockout Mice: Implications for Pulmonary Arterial Hypertension
|
---|---|
Published in |
PLOS ONE, March 2011
|
DOI | 10.1371/journal.pone.0017735 |
Pubmed ID | |
Authors |
Richard B. Rothman, Jean L. Cadet, Christina M. Dersch, Michael T. McCoy, Elin Lehrmann, Kevin G. Becker, Michael Bader, Natalia Alenina, Michael H. Baumann |
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. |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
United Kingdom | 1 | 7% |
Unknown | 14 | 93% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Researcher | 5 | 33% |
Student > Master | 3 | 20% |
Professor | 2 | 13% |
Professor > Associate Professor | 2 | 13% |
Other | 1 | 7% |
Other | 0 | 0% |
Unknown | 2 | 13% |
Readers by discipline | Count | As % |
---|---|---|
Biochemistry, Genetics and Molecular Biology | 3 | 20% |
Engineering | 3 | 20% |
Agricultural and Biological Sciences | 2 | 13% |
Pharmacology, Toxicology and Pharmaceutical Science | 1 | 7% |
Neuroscience | 1 | 7% |
Other | 1 | 7% |
Unknown | 4 | 27% |