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Gene expression in lungs of mice lacking the 5-hydroxytryptamine transporter gene
Daniel Crona1, Julie Harral, Serge Adnot
1Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, Colorado, USA. daniel.crona@uchsc.edu
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.
Insights
Pulmonary serotonin transporter (5HTT) knockout in mice alters gene expression related to inflammation and muscle function, confirming in vivo effects on vascular health. These findings highlight 5HTT's role in multiple systems impacting pulmonary vascular function.
Area of Science:
- Pulmonary vascular research
- Molecular biology
- Genetics
Background:
- Serotonin transporter (5HTT) modulation is a known risk factor for pulmonary arterial hypertension.
- Limited in vivo data exists on the molecular effects of pulmonary 5HTT inhibition.
- Previous studies suggested impacts on inflammation, proliferation, and vasoconstriction.
Purpose of the Study:
- To investigate the in vivo molecular effects of pulmonary 5HTT inhibition.
- To determine if gene expression changes support previously suggested effects on inflammation, proliferation, and vasoconstriction.
- To analyze gene expression alterations in serotonin transporter knockout mice lungs.
Main Methods:
- Assessment of right ventricular systolic pressure (RVSP) in 5-HTT knockout (5HTT-/-) and wild-type (5HTT+/+) mice.
- Lung tissue collection for RNA extraction and Affymetrix array analysis.
- Validation of key gene expression changes using quantitative RT-PCR and Western blot.
Main Results:
- No significant difference in RVSP was observed between groups.
- 124 genes showed reliable expression changes in 5HTT-/- mice compared to controls.
- Altered genes were predominantly involved in inflammatory response and muscle function, with additional changes in matrix, heme oxygenase, developmental, and energy metabolism pathways.
Conclusions:
- This study provides the first in vivo evidence of 5HTT knockout effects in the lungs.
- Downstream mechanisms suggested by ex vivo studies are confirmed to be operational in vivo.
- 5HTT impacts pulmonary vascular function through its influence on vasoreactivity, proliferation, and immune function.
