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.
BACKGROUND
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.


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-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.


CONCLUSIONS
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.
Laboratoire de Neurobiologie et de Pharmacologie Cardiovasculaire, INSERM E333, Faculté de médecine, Strasbourg, France.
Fabrice
F
Jaffré
Jacques
J
Callebert
Alexandre
A
Sarre
Nelly
N
Etienne
Canan G
CG
Nebigil
Jean-Marie
JM
Launay
Luc
L
Maroteaux
Laurent
L
Monassier
D058671:Adrenergic beta-1 Receptor Antagonists; D058672:Adrenergic beta-2 Receptor Antagonists; D000318:Adrenergic beta-Agonists / Q000633:toxicity; D000818:Animals; D006332:Cardiomegaly / Q000139:chemically induced / Q000209:etiology / Q000235:genetics / Q000503:physiopathology* / Q000517:prevention & control; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006352:Heart Ventricles / Q000166:cytology; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use*; D007375:Interleukin-1 / Q000096:biosynthesis / Q000097:blood / Q000235:genetics; D015850:Interleukin-6 / Q000096:biosynthesis / Q000097:blood / Q000235:genetics; D007545:Isoproterenol / Q000633:toxicity; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000166:cytology*; D011412:Propanolamines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D011804:Quinolines / Q000494:pharmacology* / Q000627:therapeutic use; D044403:Receptor, Serotonin, 5-HT2B / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018342:Receptors, Adrenergic, beta-1 / Q000032:analysis; D018343:Receptors, Adrenergic, beta-2 / Q000032:analysis; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000503:physiopathology*; D013566:Sympathomimetics / Q000633:toxicity; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics
D058671:Adrenergic beta-1 Receptor Antagonists; D058672:Adrenergic beta-2 Receptor Antagonists; D000318:Adrenergic beta-Agonists; D007093:Imidazoles; D007211:Indoles; D007375:Interleukin-1; D015850:Interleukin-6; D011412:Propanolamines; D011725:Pyridines; D011804:Quinolines; D044403:Receptor, Serotonin, 5-HT2B; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; C118948:SB 215505; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists; D013566:Sympathomimetics; D014409:Tumor Necrosis Factor-alpha; C026777:ICI 118551; C094868:SB 206553; C049763:CGP 20712A; D007545:Isoproterenol