Abstract
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.
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-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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adrenergic beta-1 Receptor Antagonists
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Adrenergic beta-2 Receptor Antagonists
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Adrenergic beta-Agonists / toxicity
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Animals
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Cardiomegaly / chemically induced
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Cardiomegaly / etiology
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Cardiomegaly / genetics
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Cardiomegaly / physiopathology*
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Cardiomegaly / prevention & control
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Cells, Cultured / drug effects
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Cells, Cultured / metabolism
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Drug Evaluation, Preclinical
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Fibroblasts / drug effects
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Fibroblasts / metabolism*
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / physiology
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Heart Ventricles / cytology
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Imidazoles / pharmacology
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Indoles / pharmacology*
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Indoles / therapeutic use*
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Interleukin-1 / biosynthesis
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Interleukin-1 / blood
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Interleukin-1 / genetics
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Interleukin-6 / biosynthesis
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Interleukin-6 / blood
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Interleukin-6 / genetics
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Isoproterenol / toxicity
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Mice
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Mice, Knockout
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Myocytes, Cardiac / cytology*
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Propanolamines / pharmacology
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Pyridines / pharmacology
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Pyridines / therapeutic use*
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Quinolines / pharmacology*
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Quinolines / therapeutic use
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Receptor, Serotonin, 5-HT2B / deficiency
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Receptor, Serotonin, 5-HT2B / genetics
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Receptor, Serotonin, 5-HT2B / physiology*
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Receptors, Adrenergic, beta-1 / analysis
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Receptors, Adrenergic, beta-2 / analysis
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Serotonin 5-HT2 Receptor Antagonists
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Serotonin Antagonists / pharmacology
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Serotonin Antagonists / therapeutic use*
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Sympathetic Nervous System / drug effects
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Sympathetic Nervous System / physiopathology*
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Sympathomimetics / toxicity
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Tumor Necrosis Factor-alpha / analysis
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Tumor Necrosis Factor-alpha / biosynthesis
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Tumor Necrosis Factor-alpha / genetics
Substances
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Adrenergic beta-1 Receptor Antagonists
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Adrenergic beta-2 Receptor Antagonists
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Adrenergic beta-Agonists
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Imidazoles
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Indoles
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Interleukin-1
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Interleukin-6
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Propanolamines
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Pyridines
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Quinolines
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Receptor, Serotonin, 5-HT2B
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Receptors, Adrenergic, beta-1
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Receptors, Adrenergic, beta-2
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SB 215505
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Serotonin 5-HT2 Receptor Antagonists
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Serotonin Antagonists
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Sympathomimetics
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Tumor Necrosis Factor-alpha
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ICI 118551
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SB 206553
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CGP 20712A
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Isoproterenol