title: Altered gene expression in pulmonary tissue of tryptophan hydroxylase-1 knockout mice: implications for pulmonary arterial hypertension.
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.
authors.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
authors.forename: Richard B
authors.initials: RB
authors.lastname: Rothman
authors.forename: Jean L
authors.initials: JL
authors.lastname: Cadet
authors.forename: Christina M
authors.initials: CM
authors.lastname: Dersch
authors.forename: Michael T
authors.initials: MT
authors.lastname: McCoy
authors.forename: Elin
authors.initials: E
authors.lastname: Lehrmann
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Becker
authors.forename: Michael
authors.initials: M
authors.lastname: Bader
authors.forename: Natalia
authors.initials: N
authors.lastname: Alenina
authors.forename: Michael H
authors.initials: MH
authors.lastname: Baumann
mesh_terms: D000818:Animals; D015536:Down-Regulation / Q000235:genetics; D065627:Familial Primary Pulmonary Hypertension; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D006976:Hypertension, Pulmonary / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008168:Lung / Q000201:enzymology* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D011485:Protein Binding; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D014365:Tryptophan Hydroxylase / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
chemical_list: D050486:Serotonin Plasma Membrane Transport Proteins; D014365:Tryptophan Hydroxylase