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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
3
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pubmed:dateCreated |
2011-4-5
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pubmed:abstractText |
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.
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pubmed:commentsCorrections |
http://linkedlifedata.com/resource/pubmed/commentcorrection/21464983-10841509,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21464983-10841514,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21464983-10991906,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21464983-11344128,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21464983-12244304,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21464983-12511643,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21464983-14597720,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21464983-14697203,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21464983-15078799,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21464983-15659538,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21464983-16601191,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21464983-16614302,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21464983-16644904,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21464983-17026993,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21464983-17142836,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21464983-17878933,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21464983-18032571,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21464983-18166594,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21464983-18267982,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21464983-18506000,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21464983-18723761,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21464983-18768572,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21464983-19136574,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21464983-19429774,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21464983-19505264,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21464983-8901674,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21464983-9563727
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:issn |
1932-6203
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pubmed:author |
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pubmed:issnType |
Electronic
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pubmed:volume |
6
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
e17735
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pubmed:dateRevised |
2011-11-17
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pubmed:meshHeading |
pubmed-meshheading:21464983-Animals,
pubmed-meshheading:21464983-Down-Regulation,
pubmed-meshheading:21464983-Female,
pubmed-meshheading:21464983-Gene Expression Regulation, Enzymologic,
pubmed-meshheading:21464983-Humans,
pubmed-meshheading:21464983-Hypertension, Pulmonary,
pubmed-meshheading:21464983-Lung,
pubmed-meshheading:21464983-Mice,
pubmed-meshheading:21464983-Mice, Inbred C57BL,
pubmed-meshheading:21464983-Mice, Knockout,
pubmed-meshheading:21464983-Oligonucleotide Array Sequence Analysis,
pubmed-meshheading:21464983-Protein Binding,
pubmed-meshheading:21464983-Reverse Transcriptase Polymerase Chain Reaction,
pubmed-meshheading:21464983-Serotonin Plasma Membrane Transport Proteins,
pubmed-meshheading:21464983-Tryptophan Hydroxylase,
pubmed-meshheading:21464983-Up-Regulation
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pubmed:year |
2011
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pubmed:articleTitle |
Altered gene expression in pulmonary tissue of tryptophan hydroxylase-1 knockout mice: implications for pulmonary arterial hypertension.
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pubmed:affiliation |
Translational Pharmacology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland, United States of America. rrothman@mail.nih.gov
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pubmed:publicationType |
Journal Article
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