Involvement of the Serotonin 5-HT _2B Receptor in Cardiac Hypertrophy Linked to Sympathetic Stimulation

Abstract

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 isoproterenolϩSB206553. 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.

Serotonin 5-HT 2B Receptor Blockade Prevents Reactive Oxygen Species–Induced Cardiac Hypertrophy in Mice

“…Our previous study 5 indicated that fibroblasts constitute a target of hypertrophic responses to ␤-adrenergic activation, because 5-HT 2B R blockers diminished the release of hypertrophic cytokines. We tested the effect of 5-HT 2B R blockade in O 2 ⅐Ϫ production by cardiac fibroblasts during 24-hour stimulations with Ang II or ISO.…”

“…5 After euthanasia, the heart was weighed and quickly frozen after separation of right and left ventricles and atria. In some experiments, the abdominal aorta was sampled.…”

“…Ten-to 12-week-old mouse left ventricle fibroblasts were cultured as described previously 5 and transferred to serum-free medium before a 24-hour pharmacological stimulation. Cells were treated either with serum-free culture medium only (controls) or added to Ang II (10 …”

“…We established that 5-HT 2B Rs are essential for ISO-induced cardiac hypertrophy and are involved in the regulation of hypertrophic cytokines, interleukin-6, interleukin-1␤, and TNF-␣ production by cardiac fibroblasts. 5 We hypothesized that …”

“…We established that 5-HT 2B Rs are essential for ISO-induced cardiac hypertrophy and are involved in the regulation of hypertrophic cytokines, interleukin-6, interleukin-1␤, and TNF-␣ production by cardiac fibroblasts. 5 We hypothesized that 5-HT 2B R blockade could affect NAD(P)H-oxidase function and, therefore, participate in the modulation of hypertrophic pathways implying this key enzyme.…”