doi: 10.1161/01.RES.0000225927.04710.33
© 2006 American Heart Association, Inc.
Editorials |
Serotonin Signaling in Pulmonary Hypertension
From the Division of Nephrology, Vanderbilt University Medical Center, Nashville, Tenn.
Correspondence to Mark de Caestecker, Assistant Professor, Division of Nephrology, Vanderbilt University Medical Center, S-3223, Medical Center North, 1161 21st St South, Nashville, TN 37232-2372. E-mail mark.de.Caestecker@vanderbilt.edu
See related article, pages 1323–1330
Key Words: serotonin transporter (SERT5-HTT) • pulmonary arterial hypertension • vascular smooth muscle cells • signal transduction
An extract of the first 250 words of the full text is provided, because this article has no abstract. |
Serotonin (5-HT, 5-hydroxytryptamine) has long been recognized as one of the most potent naturally occurring pulmonary vasoconstrictors.1 It was first implicated in the pathogenesis of pulmonary arterial hypertension (PAH) after an outbreak of the disease in Switzerland in the 1960’s among patients taking aminorex fumarate, an appetite suppressant that inhibits serotonin uptake by platelets.2 Since that time further outbreaks of PAH have been identified in Europe and the USA associated with the use of fenfluramine-derivate anorexigens,3–5 eventually leading to their withdrawal from the world market in 1997. Although this was, at least in retrospect, a predictable tragedy, it has ironically opened avenues of research into the biology of serotonin signaling in PAH. As fenfluramine-derivatives are substrates for the serotonin transporter (5-HTT, SERT) proteins,6 this suggests that abnormal SERT expression or functional activity could play a role in the pathogenesis of PAH. There is now a body of evidence supporting this hypothesis that provides hope for the development of effective therapeutic strategies targeting specific components of this signaling pathway in patients with these diseases.
Most of the serotonin produced in the body is secreted by enterochromaffin cells of the intestine into the portal circulation where it is partially metabolized by the liver. However, levels of free circulating serotonin are maintained in the low nanomolar range through energy-dependent SERT-mediated transport into platelets. This led some researchers to hypothesize that fenfluramines might cause PAH by increasing free plasma levels of serotonin. However, this hypothesis is inconsistent with the observation that chronic treatment with
Related Article:
Circ. Res. 2006 98: 1323-1330.
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