Abstract
BackgroundWhile 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.MethodsEight 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.ResultsRVSP 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.ConclusionThese 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.
Highlights
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
Idiopathic pulmonary arterial hypertension (IPAH) is a disease characterized by pulmonary vasoconstriction, inflammation, and vascular remodeling, whose early events and molecular etiology are still obscure
Dexfenfluramine, which is the active enantiomer of fenfluramine and used to treat obesity in patients, was considered to be the chief culprit behind the increase in cases of pulmonary hypertension[2,3]
Summary
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. Idiopathic pulmonary arterial hypertension (IPAH) is a disease characterized by pulmonary vasoconstriction, inflammation, and vascular remodeling, whose early events and molecular etiology are still obscure. Dexfenfluramine, which is the active enantiomer of fenfluramine and used to treat obesity in patients, was considered to be the chief culprit behind the increase in cases of pulmonary hypertension[2,3]. Dexfenfluramine acts as a substrate for the serotonin transporter (5HTT), causing increased extracellular 5-HT by a mechanism involving exchange of drug molecules for intracellular 5-HT[4]. Dexfenfluramine causes overexpression of 5-HTT, but with the net effect of increased available 5HT[3,5]
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