Published Online
on April 12, 2004

A more recent version of this article appeared on May 4, 2004

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Submitted on October 2, 2003
Revised on January 6, 2004
Accepted on January 27, 2004

Overexpression of the 5-Hydroxytryptamine Transporter Gene. Effect on Pulmonary Hemodynamics and Hypoxia-Induced Pulmonary Hypertension

Margaret R. MacLean PhD^*, Graeme A. Deuchar PhD, Martin N. Hicks PhD, Ian Morecroft PhD, Sanbing Shen PhD, John Sheward PhD, Janet Colston PhD, Lynn Loughlin , Margaret Nilsen , Yvonne Dempsie PhD, and Anthony Harmar PhD

From the Institute of Biomedical and Life Sciences (M.R.M., I.M., J.C., L.L., M.N., Y.D.) and Department of Medical Cardiology (G.A.D., M.N.H.), Glasgow University, and the Division of Neuroscience, University of Edinburgh (A.H., S.S., J.S.), UK.

^* To whom correspondence should be addressed. E-mail: m.maclean{at}bio.gla.ac.uk.

Background--Increased serotonin (5-hydroxytryptamine, 5-HT) transporter activity has been observed in human familial pulmonary hypertension.

Methods and 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.

Key words: hypertension, pulmonary • hypoxia • remodeling • risk factors • genes

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