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(Circulation. 2004;110:969-974.)
© 2004 American Heart Association, Inc.

Original Articles

Involvement of the Serotonin 5-HT_2B Receptor in Cardiac Hypertrophy Linked to Sympathetic Stimulation

Control of Interleukin-6, Interleukin-1ß, and Tumor Necrosis Factor- Cytokine Production by Ventricular Fibroblasts

Fabrice Jaffré, MS; Jacques Callebert, PharmD, PhD; Alexandre Sarre, MS; Nelly Etienne, MS; Canan G. Nebigil, PharmD, PhD; Jean-Marie Launay, PharmD, PhD; Luc Maroteaux, PhD; Laurent Monassier, MD, PhD

From the Laboratoire de Neurobiologie et de Pharmacologie Cardiovasculaire, INSERM E333, Faculté de médecine, Strasbourg (A.S., L. Monassier); Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS, INSERM, Université L. Pasteur de Strasbourg, Illkirch (F.J., N.E., C.G.N., L. Maroteaux); and Centre de Recherches Claude Bernard, Service de Biochimie, Hôpital Lariboisière, Paris (J.C., J.-M.L.), France.

Correspondence to Laurent Monassier, MD, PhD, Laboratoire de Neurobiologie et de Pharmacologie Cardiovasculaire, INSERM E333, Faculté de médecine, 11 rue Humann, 67085 Strasbourg, France. E-mail laurent.monassier{at}medecine.u-strasbg.fr

Received October 29, 2003; de novo received January 24, 2004; revision received March 16, 2004; accepted March 23, 2004.

Background— The serotonergic 5-HT_2B receptor regulates cardiomyocyte development and growth. A putative contribution of this receptor to fibroblast-dependent cardiac function has not been identified.

Methods and Results— By mimicking sympathetic stimulation with chronic isoproterenol perfusion in vivo, we found that mice developed a cardiac hypertrophy, which was prevented by exposure to the 5-HT_2B receptor antagonists SB206553 or SB215505 or in 5-HT_2B receptor–knockout mice. The isoproterenol-induced hypertrophy was associated with an increase in the plasma levels of interleukin-1ß and tumor necrosis factor- but not interleukin-6. In contrast, the plasma isoproterenol-induced cytokine increase was not observed in either 5-HT_2B receptor–mutant or wild-type mice perfused with isoproterenol+SB206553. We demonstrated that stimulation of wild-type cardiac fibroblasts by isoproterenol markedly increased the production of the interleukin-6, interleukin-1ß, and tumor necrosis factor- cytokines. Strikingly, we found that this isoproterenol-induced cytokine production was abolished by SB206553 or in 5-HT_2B receptor–knockout fibroblasts. Serotonin also stimulated production of the 3 cytokines in wild-type fibroblasts, which was effectively reduced in 5-HT_2B receptor–knockout fibroblasts.

Conclusions— Our results demonstrate for the first time that 5-HT_2B receptors are essential for isoproterenol-induced cardiac hypertrophy, which involves the regulation of interleukin-6, interleukin-1ß, and tumor necrosis factor- cytokine production by cardiac fibroblasts.

Key Words: fibroblasts • hypertrophy • interleukins • nervous system, sympathetic • remodeling

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