Key result
5-HT2B receptor antagonism or knockout prevented isoproterenol-induced cardiac hypertrophy and abolished the associated increase in pro-inflammatory cytokines.
Why the study?
Does 5-HT2B receptor antagonism prevent isoproterenol-induced cardiac hypertrophy and cytokine production in mice?
Does 5-HT2B receptor antagonism prevent isoproterenol-induced cardiac hypertrophy and cytokine production in mice?
The 5-HT2B receptor is essential for isoproterenol-induced cardiac hypertrophy and regulates cytokine production by cardiac fibroblasts.
Hypothesis-generating for 5-HT2B blockade in sympathetic hypertrophy; human translation requires prospective trials.
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.
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Jaffré et al. (2004) studied Cardiac hypertrophy. 5-HT2B receptor antagonists (SB206553 or SB215505) or 5-HT2B receptor knockout vs. Wild-type mice or no antagonist was evaluated on Isoproterenol-induced cardiac hypertrophy and cytokine production. 5-HT2B receptor antagonism or knockout prevented isoproterenol-induced cardiac hypertrophy and abolished the associated increase in pro-inflammatory cytokines.
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