Overexpression of the 5-hydroxytryptamine transporter gene: effect on pulmonary hemodynamics and hypoxia-induced pulmonary hypertension.
BACKGROUND
Increased serotonin (5-hydroxytryptamine, 5-HT) transporter activity has been observed in human familial pulmonary hypertension.


RESULTS
We investigated pulmonary hemodynamics and the development of hypoxia-induced pulmonary hypertension and pulmonary vascular remodeling in mice overexpressing the gene for the 5-HT transporter (5-HTT+ mice). Right ventricular pressure was elevated 3-fold in normoxic 5-HTT+ mice compared with their wild-type controls. Hypoxia-induced increases in right ventricular hypertrophy and pulmonary vascular remodeling were also potentiated in the 5-HTT+ mice. 5-HTT-like immunoreactivity, protein, and binding sites were markedly increased in the lungs from the 5-HTT+ mice. Hypoxia, however, decreased 5-HT transporter immunoreactivity, mRNA transcription, protein, and binding sites in both wild-type and 5-HTT+ mice.


CONCLUSIONS
Increased 5-HT transporter expression causes elevated right ventricular pressures, and this occurs before the onset of right ventricular hypertrophy or pulmonary arterial remodeling. Hypoxia-induced remodeling is, however, increased in 5-HTT+ mice, whereas hypoxia inhibits 5-HTT expression. This provides a unique model that demonstrates differential mechanisms for familial pulmonary arterial hypertension and pulmonary arterial hypertension with hypoxemia.
MacLean
Margaret R
MR
Institute of Biomedical and Life Sciences, University of Glasgow, Scotland, UK. m.maclean@bio.gla.ac.uk
Deuchar
Graeme A
GA
Hicks
Martin N
MN
Morecroft
Ian
I
Shen
Sanbing
S
Sheward
John
J
Colston
Janet
J
Loughlin
Lynn
L
Nilsen
Margaret
M
Dempsie
Yvonne
Y
Harmar
Anthony
A
D000818:Animals; D001665:Binding Sites; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D015283:Citalopram / Q000378:metabolism; D015870:Gene Expression; D006439:Hemodynamics; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000235:genetics*; D017380:Hypertrophy, Right Ventricular / Q000209:etiology / Q000235:genetics*; D000860:Hypoxia / Q000150:complications*; D008168:Lung / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology*; D026901:Membrane Transport Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D011651:Pulmonary Artery / Q000473:pathology*; D012333:RNA, Messenger / Q000096:biosynthesis; D012307:Risk Factors; D050486:Serotonin Plasma Membrane Transport Proteins; D013997:Time Factors
D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; D015283:Citalopram