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(Chest. 2005;128:552S-553S.)
© 2005 American College of Chest Physicians

Serotonin Transporter and Receptors in Various Forms of Human Pulmonary Hypertension*

Elisabeth Marcos, MD; Elie Fadel, MD; Olivier Sanchez, MD; Marc Humbert, MD; Philippe Dartevelle, MD; Gerald Simonneau, MD; Michel Hamon, MD; Serge Adnot, MD and Saadia Eddahibi, PhD

* From INSERM U492 and Service de Physiologie Explorations Fonctionnelles (Drs. Marcos, Sanchez, Adnot, and Eddahibi), Hôpital H. Mondor, Créteil; INSERM U288 (Dr. Hamon), NeuroPsychoPharmacologie Moléculaire, Cellulaire et Fonctionnelle; Faculté de Médecine Pitié-Salpêtrière, Paris; UPRES EA2705 (Drs. Fadel and Dartevelle), Service de Pneumologie, Hôpital A. Béclère, Clamart; and UPRES EA2705 (Drs. Humbert and Simonneau), Service de Chirurgie Thoracique, Vasculaire et de Transplantation Cardiopulmonaire, Hôpital Marie Lannelongue, Le Plessis Robinson, France.

Correspondence to: Saadia Eddahibi, INSERM U492, Faculté de Médecine, 8, Avenue Général Sarrail, 94010 Créteil, France; e-mail: saadia.eddahibi{at}creteil.inserm.fr

Some recent studies1 have emphasized the major role of serotonin (5-hydroxytryptamine [5-HT]) in the process of pulmonary vascular remodeling. An increased risk of primary pulmonary hypertension (PPH) has been reported in patients who used appetite suppressants acting on the 5-HT transporter (5-HTT). However, the mechanism by which 5-HT affects the pulmonary vasculature is still a matter of debate. Although we previously showed that 5-HTT overexpression was associated with pulmonary vascular smooth-muscle hyperplasia in patients with PPH,2 studies in relevant animal models provided evidence that not only the 5-HTT,34 but also several 5-HT receptors, namely 5-HT-1B,5 5-HT-2A, and 5-HT-2B,6 may contribute to the pulmonary vascular remodeling process. However, the respective contributions of 5-HT receptors and the 5-HTT in human pulmonary hypertension (PH) have not been specifically examined. Moreover, another key issue is whether alterations in the serotonin signaling pathway may be a common pathogenic mechanism in various forms of PH.

Here we investigated the expression of the 5-HTT and the 5-HT-1B, 5-HT-2A, and 5-HT-2B receptors in lungs and isolated pulmonary artery smooth-muscle cells (PA-SMCs) from patients with PH and control subjects.7 The respective roles of 5-HTT and 5-HT-1B, 5-HT-2A, and 5-HT-2B receptors on PA-SMC proliferation were assessed in cells from both patients with PH and control subjects using selective 5-HTT inhibitors and 5-HT receptor antagonists. We found that 5-HTT inhibitors, but not 5-HT receptor antagonists, influenced the PA-SMC growth response to 5-HT, and we consequently examined 5-HTT expression and its effects on PA-SMC growth in patients with various types of PH, namely PPH (n = 14), secondary PH (SPH) [n = 8], and pulmonary veno-occlusive disease (n = 4). Because 5-HTT expression is genetically controlled, we characterized the genotype of cells from both patients and control subjects and investigated whether promoter sequence alterations or modifications in signaling pathways underlie 5-HTT overexpression in patients with PH.

Whereas strong immunostaining for the three receptor types and 5-HTT was seen in remodeled pulmonary vessels from patients in all PH categories, only 5-HTT expression was increased in cultured PA-SMCs from patients vs control subjects. The increased growth response of PA-SMCs from patients with PPH, pulmonary veno-occlusive disease, or SPH to 5-HT or serum seemed entirely ascribable to 5-HTT overexpression, since 5-HTT inhibitors but not 5-HT receptor antagonists abolished 5-HT mitogenic activity and reduced the serum-induced growth response to similar levels in patients as in control subjects. PA-SMCs from patients with PH showed higher 5-HTT messenger RNA levels than those from control subjects but expressed similar luciferase activity when transfected with a 5-HTT promoter-luciferase gene construct. The L-allelic variant of the 5-HTT gene promoter, which is associated with 5-HTT overexpression, was present homozygously in 14 of 25 of lung transplanted patients (56%) with SPH, but in only 27% of control subjects. Polymorphism of the 5-HTT gene promoter was only partly responsible for the increased 5-HTT expression in PH, since PA-SMCs from patients exhibited higher 5-HTT levels than same-genotype cells from control subjects and no additional promoter sequence alterations were found. We conclude that 5-HTT overexpression is a common pathogenic mechanism in various forms of PH that is only partly related to 5-HTT gene polymorphism.


   Footnotes
 
Abbreviations: 5-HHT = 5-hydroxytryptamine transporter; 5-HT = 5-hydroxytryptamine; PA-SMC = pulmonary artery smooth-muscle cell; PH = pulmonary hypertension; PPH = primary pulmonary hypertension; SPH = secondary pulmonary hypertension


   References
TOP
 References
 

  1. Abenhaim, L, Moride, Y, Brenot, F, et al (1996) Appetite-suppressant drugs and the risk of primary pulmonary hypertension. International Primary Pulmonary Hypertension Study Group. N Engl J Med 335,609-616[Abstract/Free Full Text]
  2. Eddahibi, S, Humbert, M, Fadel, E, et al Serotonin transporter overexpression is responsible for pulmonary artery smooth muscle hyperplasia in primary pulmonary hypertension. J Clin Invest 2001;108,1141-1150[CrossRef][ISI][Medline]
  3. Eddahibi, S, Fabre, V, Boni, C, et al Induction of serotonin transporter by hypoxia in pulmonary vascular smooth muscle cells: relationship with the mitogenic action of serotonin. Circ Res 1999;84,329-336[Abstract/Free Full Text]
  4. Eddahibi, S, Hanoun, N, Lanfumey, L, et al Attenuated hypoxic pulmonary hypertension in mice lacking the 5-hydroxytryptamine transporter gene. J Clin Invest 2000;105,1555-1562[ISI][Medline]
  5. Keegan, A, Morecroft, I, Smillie, D, et al Contribution of the 5-HT1B receptor to hypoxia-induced pulmonary hypertension. Circ Res 2001;89,1231-1239[Abstract/Free Full Text]
  6. Launay, JM, Herve, P, Peoc’h, K, et al Function of the serotonin 5-hydroxytryptamine 2B receptor in pulmonary hypertension. Nat Med 2002;8,1129-1135[CrossRef][ISI][Medline]
  7. Marcos, E, Fadel, E, Sanchez, O, et al Serotonin-induced smooth muscle hyperplasia in various forms of human pulmonary hypertension. Circ Res 2004;94,1263-1270[Abstract/Free Full Text]




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