HAL : inserm-00499643, version 1

PubMed : 15927991

DOI : 10.1161/CIRCULATIONAHA.104.524926

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Circulation 111, 21 (2005) 2812-9

Serotonin transporter inhibition prevents and reverses monocrotaline-induced pulmonary hypertension in rats.

Christophe Guignabert (  Auteur correspondant ) 1, 2, Bernadette Raffestin 3, Rima Benferhat 1, 2, William Raoul 1, Patricia Zadigue 1, 2, Dominique Rideau 1, 2, Michel Hamon 4, Serge Adnot 1, 2, Saadia Eddahibi 1, 2

(31/05/2005)

BACKGROUND: Progression of pulmonary hypertension (PH) is associated with increased lung expression of the serotonin transporter (5-HTT), which leads to hyperplasia of the pulmonary artery smooth muscle cells (PA-SMCs). Given the postulated causal relation between 5-HTT overexpression and PH, we herein investigated whether the highly selective 5-HTT inhibitor fluoxetine prevented and/or reversed PH induced by monocrotaline (MCT) in rats. Selective 5-HT(1B/1D), 5-HT(2A), and 5-HT(2B) receptor antagonists were used for comparative testing. METHODS AND RESULTS: MCT injection (60 mg/kg SC) was followed by an early peak in lung 5-HTT expression on day 1, which preceded the onset of PH. Established PH on day 15 was associated with a sustained 5-HTT increase. Continued fluoxetine treatment completely prevented PA-SMC proliferation and PH development and also suppressed the late 5-HTT increase, without affecting the early peak. The 5-HT receptor antagonists did not affect PH. Fluoxetine (10 mg . kg(-1) . d(-1) PO) started 3 weeks after MCT injection completely reversed established PH, normalizing PA pressure and structure. MCT-induced PH was also associated with increased expression of various cytokines, but only interleukin-1beta and monocyte chemotactic protein-1 increased at the early phase and stimulated 5-HTT expression by cultured PA-SMCs. CONCLUSIONS: Upregulation of lung 5-HTT induced by MCT appears necessary to initiate the development of pulmonary vascular remodeling, whereas a sustained increase in 5-HTT expression may underlie both the progression and the maintenance of MCT-induced PH. Complete reversal of established PH by fluoxetine provides a rationale for new therapeutic strategies in human PH.

1 :	Physiopathologie et Thérapeutiques Respiratoires
	INSERM : U492 – IFR10
2 :	Service de chirurgie thoracique et d'anatomopathologie
	Assistance publique - Hôpitaux de Paris (AP-HP) – Hôpital Hôtel Dieu
3 :	Département de physiologie
	Assistance publique - Hôpitaux de Paris (AP-HP) – Hôpital Ambroise Paré – Université Paris V - Paris Descartes
4 :	Neuropsychopharmacologie moléculaire, cellulaire et fonctionnelle
	INSERM : U288 – Université Pierre et Marie Curie [UPMC] - Paris VI

domaine

:

Sciences du Vivant/Biologie cellulaire Sciences du Vivant/Médecine humaine et pathologie/Pneumologie et système respiratoire Sciences du Vivant/Médecine humaine et pathologie/Cardiologie et système cardiovasculaire Sciences du Vivant/Médecine humaine et pathologie/Physiologie Sciences du Vivant/Biologie animale Sciences du Vivant/Médecine humaine et pathologie Chimie/Chimie thérapeutique

mots-clés auteur : pulmonary heart disease – remodeling – muscle – smooth

inserm-00499643, version 1

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Contributeur : Christophe Guignabert <>

Soumis le : Dimanche 11 Juillet 2010, 16:05:23

Dernière modification le : Mardi 13 Juillet 2010, 09:23:33