Involvement of the serotonin 5-HT2B receptor in cardiac hypertrophy linked to sympathetic stimulation: control of interleukin-6, interleukin-1beta, and tumor necrosis factor-alpha cytokine production by ventricular fibroblasts.

Fabrice Jaffré (1) , Jacques Callebert (2) , Alexandre Sarre (3) , Nelly Etienne (1) , Canan G Nebigil (1) , Jean-Marie Launay (2) , Luc Maroteaux (1) , Laurent Monassier (3)

1 Institut du Fer à Moulin
2 Service de Biochimie et de Biologie moléculaire
3 LNPCV - Laboratoire de neurobiologie et pharmacologie cardiovasculaire

The serotonergic 5-HT2B receptor regulates cardiomyocyte development and growth. A putative contribution of this receptor to fibroblast-dependent cardiac function has not been identified. 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-HT2B receptor antagonists SB206553 or SB215505 or in 5-HT2B receptor-knockout mice. The isoproterenol-induced hypertrophy was associated with an increase in the plasma levels of interleukin-1beta and tumor necrosis factor-alpha but not interleukin-6. In contrast, the plasma isoproterenol-induced cytokine increase was not observed in either 5-HT2B 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-1beta, and tumor necrosis factor-alpha cytokines. Strikingly, we found that this isoproterenol-induced cytokine production was abolished by SB206553 or in 5-HT2B receptor-knockout fibroblasts. Serotonin also stimulated production of the 3 cytokines in wild-type fibroblasts, which was effectively reduced in 5-HT2B receptor-knockout fibroblasts. Our results demonstrate for the first time that 5-HT2B receptors are essential for isoproterenol-induced cardiac hypertrophy, which involves the regulation of interleukin-6, interleukin-1beta, and tumor necrosis factor-alpha cytokine production by cardiac fibroblasts.

Domaines: Pharmacologie; Neurobiologie; Cardiologie et système cardiovasculaire; Psychiatrie et santé mentale; Pneumologie et système respiratoire; Génétique animale; Biologie moléculaire

Fabrice Jaffré, Jacques Callebert, Alexandre Sarre, Nelly Etienne, Canan G Nebigil, et al.. Involvement of the serotonin 5-HT2B receptor in cardiac hypertrophy linked to sympathetic stimulation: control of interleukin-6, interleukin-1beta, and tumor necrosis factor-alpha cytokine production by ventricular fibroblasts.. Circulation, 2004, 110 (8), pp.969-974. ⟨10.1161/01.CIR.0000139856.20505.57⟩. ⟨hal-01274954⟩