Published Online
on August 9, 2004

A more recent version of this article appeared on August 24, 2004

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Submitted on October 29, 2003
Revised on March 16, 2004
Accepted on March 23, 2004

Involvement of the Serotonin 5-HT_2B Receptor in Cardiac Hypertrophy Linked to Sympathetic Stimulation. Control of Interleukin-6, Interleukin-1, 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, and 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.

^* To whom correspondence should be addressed. E-mail: laurent.monassier{at}medecine.u-strasbg.fr.

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-1 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-1, 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-1, and tumor necrosis factor- cytokine production by cardiac fibroblasts.

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

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