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Open Access Research article

Gene expression in lungs of mice lacking the 5-hydroxytryptamine transporter gene

Daniel Crona1, Julie Harral1, Serge Adnot2, Saadia Eddahibi2 and James West3*

Author Affiliations

1 Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, Colorado, USA

2 INSERM U841 and Département de Physiologie Explorations Fonctionnelles, Hôpital H. Mondor, AP-HP, Créteil, France

3 Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University, Nashville, Tennessee, USA

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BMC Pulmonary Medicine 2009, 9:19  doi:10.1186/1471-2466-9-19

Published: 10 May 2009

Abstract

Background

While modulation of the serotonin transporter (5HTT) has shown to be a risk factor for pulmonary arterial hypertension for almost 40 years, there is a lack of in vivo data about the broad molecular effects of pulmonary inhibition of 5HTT. Previous studies have suggested effects on inflammation, proliferation, and vasoconstriction. The goal of this study was to determine which of these were supported by alterations in gene expression in serotonin transporter knockout mice.

Methods

Eight week old normoxic mice with a 5-HTT knock-out (5HTT-/-) and their heterozygote(5HTT+/-) or wild-type(5HTT+/+) littermates had right ventricular systolic pressure(RVSP) assessed, lungs collected for RNA, pooled, and used in duplicate in Affymetrix array analysis. Representative genes were confirmed by quantitative RT-PCR and western blot.

Results

RVSP was normal in all groups. Only 124 genes were reliably changed between 5HTT-/- and 5HTT+/+ mice. More than half of these were either involved in inflammatory response or muscle function and organization; in addition, some matrix, heme oxygenase, developmental, and energy metabolism genes showed altered expression. Quantitative RT-PCR for examples from each major group confirmed changes seen by array, with an intermediate level in 5HTT +/- mice.

Conclusion

These results for the first time show the in vivo effects of 5HTT knockout in lungs, and show that many of the downstream mechanisms suggested by cell culture and ex vivo experiments are also operational in vivo. This suggests that the effect of 5HTT on pulmonary vascular function arises from its impact on several systems, including vasoreactivity, proliferation, and immune function.