doi: 10.1161/CIRCULATIONAHA.104.524926
(Circulation. 2005;111:2812-2819.)
© 2005 American Heart Association, Inc.
Vascular Medicine |
Serotonin Transporter Inhibition Prevents and Reverses Monocrotaline-Induced Pulmonary Hypertension in Rats
From the Département de Physiologie (C.G., R.B., P.Z., D.R., S.A., S.E.), INSERM U492, AP-HP, CHU Henri Mondor, Créteil; the Département de Physiologie (B.R.), Université René Descartes, Hôpital Ambroise Paré, AP-HP, UER Paris ouest, Boulogne; and INSERM U288 (M.H.), NeuroPsychoPharmacologie Moléculaire, Cellulaire et Fonctionnelle, Faculté de Médecine Pitié-Salpêtrière, Paris, France.
Correspondence to Saadia Eddahibi, PhD, INSERM U492, Faculté de Médecine, Créteil, France. E-mail saadia.eddahibi{at}creteil.inserm.fr
Received November 26, 2003; de novo received August 24, 2004; revision received November 26, 2004; accepted January 11, 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-HT1B/1D, 5-HT2A, and 5-HT2B 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-1ß and monocyte chemotactic protein-1 increased at the early phase and stimulated 5-HTT expression by cultured PA-SMCs.
Conclusion— 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.
Key Words: pulmonary heart disease • remodeling • muscle, smooth
This article has been cited by other articles:
 |
|
 |
|
  M. Izikki, B. Raffestin, J. Klar, A. Hatzelmann, D. Marx, H. Tenor, P. Zadigue, S. Adnot, and S. Eddahibi Effects of Roflumilast, a Phosphodiesterase-4 Inhibitor, on Hypoxia- and Monocrotaline-Induced Pulmonary Hypertension in Rats J. Pharmacol. Exp. Ther., July 1, 2009; 330(1): 54 - 62. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. M. Hassoun, L. Mouthon, J. A. Barbera, S. Eddahibi, S. C. Flores, F. Grimminger, P. L. Jones, M. L. Maitland, E. D. Michelakis, N. W. Morrell, et al. Inflammation, growth factors, and pulmonary vascular remodeling. J. Am. Coll. Cardiol., June 30, 2009; 54(1 Suppl): S10 - S19. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. W. Morrell, S. Adnot, S. L. Archer, J. Dupuis, P. Lloyd Jones, M. R. MacLean, I. F. McMurtry, K. R. Stenmark, P. A. Thistlethwaite, N. Weissmann, et al. Cellular and molecular basis of pulmonary arterial hypertension. J. Am. Coll. Cardiol., June 30, 2009; 54(1 Suppl): S20 - S31. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Dempsie, I. Morecroft, D. J. Welsh, N. A. MacRitchie, N. Herold, L. Loughlin, M. Nilsen, A. J. Peacock, A. Harmar, M. Bader, et al. Converging Evidence in Support of the Serotonin Hypothesis of Dexfenfluramine-Induced Pulmonary Hypertension With Novel Transgenic Mice Circulation, June 3, 2008; 117(22): 2928 - 2937. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. K. Weir, M. Obreztchikova, and Z. Hong Fenfluramine: riddle or Rosetta stone? Eur. Respir. J., February 1, 2008; 31(2): 232 - 235. [Full Text] [PDF]
|
|
|
|
 |
|
 E. Fornaro, D. Li, J. Pan, and J. Belik Prenatal Exposure to Fluoxetine Induces Fetal Pulmonary Hypertension in the Rat Am. J. Respir. Crit. Care Med., November 15, 2007; 176(10): 1035 - 1040. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Laudi, S. Trump, V. Schmitz, J. West, I. F. McMurtry, H. Mutlak, U. Christians, J. Weimann, U. Kaisers, and W. Steudel Serotonin transporter protein in pulmonary hypertensive rats treated with atorvastatin Am J Physiol Lung Cell Mol Physiol, September 1, 2007; 293(3): L630 - L638. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. B. Sehgal, S. Mukhopadhyay, F. Xu, K. Patel, and M. Shah Dysfunction of Golgi tethers, SNAREs, and SNAPs in monocrotaline-induced pulmonary hypertension Am J Physiol Lung Cell Mol Physiol, June 1, 2007; 292(6): L1526 - L1542. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. F. Wideman, M. E. Chapman, K. R. Hamal, O. T. Bowen, A. G. Lorenzoni, G. F. Erf, and N. B. Anthony An Inadequate Pulmonary Vascular Capacity and Susceptibility to Pulmonary Arterial Hypertension in Broilers Poult. Sci., May 1, 2007; 86(5): 984 - 998. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Liu, H. Liu, G. Visner, and B. S. Fletcher Sleeping Beauty-mediated eNOS gene therapy attenuates monocrotaline-induced pulmonary hypertension in rats FASEB J, December 1, 2006; 20(14): 2594 - 2596. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. A. Ghofrani, R. Voswinckel, F. Reichenberger, N. Weissmann, R. T. Schermuly, W. Seeger, and F. Grimminger Hypoxia- and non-hypoxia-related pulmonary hypertension - Established and new therapies Cardiovasc Res, October 1, 2006; 72(1): 30 - 40. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Bonnet, E. D. Michelakis, C. J. Porter, M. A. Andrade-Navarro, B. Thebaud, S. Bonnet, A. Haromy, G. Harry, R. Moudgil, M. S. McMurtry, et al. An Abnormal Mitochondrial-Hypoxia Inducible Factor-1{alpha}-Kv Channel Pathway Disrupts Oxygen Sensing and Triggers Pulmonary Arterial Hypertension in Fawn Hooded Rats: Similarities to Human Pulmonary Arterial Hypertension Circulation, June 6, 2006; 113(22): 2630 - 2641. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. de Caestecker Serotonin Signaling in Pulmonary Hypertension Circ. Res., May 26, 2006; 98(10): 1229 - 1231. [Full Text] [PDF]
|
|
|
|
|
|
C. Guignabert, M. Izikki, L. I. Tu, Z. Li, P. Zadigue, A.-M. Barlier-Mur, N. Hanoun, D. Rodman, M. Hamon, S. Adnot, et al. Transgenic Mice Overexpressing the 5-Hydroxytryptamine Transporter Gene in Smooth Muscle Develop Pulmonary Hypertension Circ. Res., May 26, 2006; 98(10): 1323 - 1330. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Cogolludo, L. Moreno, F. Lodi, G. Frazziano, L. Cobeno, J. Tamargo, and F. Perez-Vizcaino Serotonin Inhibits Voltage-Gated K+ Currents in Pulmonary Artery Smooth Muscle Cells: Role of 5-HT2A Receptors, Caveolin-1, and KV1.5 Channel Internalization Circ. Res., April 14, 2006; 98(7): 931 - 938. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. D. Willers, J. H. Newman, J. E. Loyd, I. M. Robbins, L. A. Wheeler, M. A. Prince, K. C. Stanton, J. A. Cogan, J. R. Runo, D. Byrne, et al. Serotonin Transporter Polymorphisms in Familial and Idiopathic Pulmonary Arterial Hypertension Am. J. Respir. Crit. Care Med., April 1, 2006; 173(7): 798 - 802. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. M. Hoeper and L. J. Rubin Update in pulmonary hypertension 2005. Am. J. Respir. Crit. Care Med., March 1, 2006; 173(5): 499 - 505. [Full Text] [PDF]
|
|