Involvement of the serotonin 5-HT2B receptor in cardiac hypertrophy linked to sympathetic stimulation control of interleukin-6, interleukin-1β, and tumor necrosis factor-α cytokine production by ventricular fibroblasts
Involvement of the serotonin 5-HT2B receptor in cardiac hypertrophy linked to sympathetic stimulation control of interleukin-6, interleukin-1β, and tumor necrosis factor-α cytokine production by ventricular fibroblasts
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DOI：
10.1161/01.cir.0000139856.20505.57
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发表时间：
2004-08-24
期刊：
影响因子：
37.8
通讯作者：
Monassier, L
中科院分区：
文献类型：
--
作者：
Jaffré, F;Callebert, J;Monassier, L
背景-肾上腺素能5-HT 2B受体调节心肌细胞的发育和生长。一个假定的贡献，这种受体成纤维细胞依赖的心脏功能尚未被identified.Methods和结果-通过模仿交感神经刺激与慢性异丙肾上腺素灌注在体内，我们发现，小鼠开发了心脏肥大，这是防止暴露于5-HT 2B受体拮抗剂SB 206553或SB 215505或在5-HT 2B受体敲除小鼠。异丙肾上腺素诱导的肥大与白细胞介素-1 β和肿瘤坏死因子-α的血浆水平升高有关，但与白细胞介素-6无关。相反，在用异丙肾上腺素+SB 206553灌注的5-HT 2B受体突变体或野生型小鼠中均未观察到血浆异丙肾上腺素诱导的细胞因子增加。我们证明，异丙肾上腺素刺激野生型心脏成纤维细胞显著增加白细胞介素-6，白细胞介素-1 β和肿瘤坏死因子-α细胞因子的产生。引人注目的是，我们发现这种异丙肾上腺素诱导的细胞因子产生被SB 206553或在5-HT 2B受体敲除的成纤维细胞中消除。5-羟色胺也刺激生产的3种细胞因子在野生型成纤维细胞，这是有效地减少在5-HT 2B受体敲除fibroblast.Conclusions -我们的研究结果表明，第一次，5-HT 2B受体是必不可少的异丙肾上腺素诱导的心脏肥大，这涉及到调节白细胞介素-6，白细胞介素-1 β，和肿瘤坏死因子-α细胞因子生产的心脏成纤维细胞。
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.