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Hyperplasia of Pulmonary Artery Smooth Muscle Cells Is Causally Related to Overexpression of the Serotonin Transporter in Primary Pulmonary Hypertension* FREE TO VIEW

Saadia Eddahibi, PhD; Marc Humbert, MD, PhD; Elie Fadel, MD; Bernadette Raffestin, MD, PhD; Michèle Darmon, PhD; Frédérique Capron, MD, PhD; Gérald Simonneau, MD, PhD; Philippe Dartevelle, MD, PhD; Michel Hamon, PhD; Serge Adnot, MD, PhD
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*From INSERM U492 et Departement de Physiologie (Drs. Eddahibi, Raffestin, and Adnot), Créteil, France; Service de Pneumologie (Drs. Humbert, Capron, and Simonneau), Clamart France; INSERM U288 (Drs. Darmon and Hamon), Paris, France; and Service de Chirurgie Thoracique (Drs. Fadel and Dartevelle), Le Plessis Robinson, France.

Correspondence to: Serge Adnot, MD, PhD, INSERM Unité 492, Faculté de Médecine, 8, rue du Général Sarrail, 94010 Créteil Cedex, France; e-mail: secr.u492@im3.inserm.fr

Chest. 2002;121(3_suppl):97S-98S. doi:10.1378/chest.121.3_suppl.97S
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Hyperplasia of pulmonary artery smooth muscle cells (PA-SMCs) is a hallmark pathologic feature of primary pulmonary hypertension (PPH). Herein, we found that PA-SMCs from patients with PPH grow faster than those from control subjects when stimulated by serotonin or serum and that these effects are due to the increased expression of the serotonin transporter, which mediates the internalization of indolamine. The increased growth responsiveness of PA-SMCs from patients with PPH was selective to serotonin since it did not occur with growth factors such as epidermal growth factor, transforming growth factor-β, fibroblast growth factor, or platelet-derived growth factor. In the presence of 5-HTT inhibitors, the growth stimulatory effects of serum and serotonin were markedly reduced, and the difference between the growth of PA-SMCs between patients and control subjects was no longer observed. The expression of 5-HTT was increased in cultured cells from patients with PPH compared to those from control subjects, with an increase of two to three times in 5-HTT messenger RNA, 5-HTT protein, and 5-HTT uptake activity. Increased 5-HTT expression also was found in the platelets and lungs of patients with PPH in whom it predominated in the media of thickened pulmonary arteries and in onion-bulb lesions. Because a 5-HTT-linked promoter region insertion/deletion polymorphism with long (L) and short forms affects 5-HTT expression and function, we additionally examined the role of this polymorphism in PPH. Cells homozygous for the L variant showed increased 5-HTT expression and increased growth responses to 5-HT and serum. In a population of 89 patients with PPH and 84 control subjects, we found that the biallelic LL condition was present in 65% of the patients with PPH compared to 27% of the control subjects. These results indicate that 5-HTT plays a key role in the pathogenesis of PA-SMC proliferation in patients with PPH and that the L variant of the 5-HTT gene polymorphism represents a genetic susceptibility for developing PPH.

Abbreviations: L = long; PA-SMC = pulmonary artery smooth muscle cell; PPH = primary pulmonary hypertension




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