Ablation of serotonin 5-HT2B receptors in mice leads to abnormal cardiac structure and function
Ablation of serotonin 5-HT2B receptors in mice leads to abnormal cardiac structure and function
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DOI：
10.1161/01.cir.103.24.2973
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发表时间：
2001-06-19
期刊：
影响因子：
37.8
通讯作者：
Maroteaux, L
中科院分区：
文献类型：
--
作者：
Nebigil, CG;Hickel, P;Maroteaux, L
背景-识别调节心肌结构和功能的因素对于了解心脏病的发病机制很重要。由于对5-羟色胺引发的心脏功能的分子机制知之甚少，其受体的下游信号通路与心脏生理之间的联系引起了广泛的兴趣。小鼠体内的5-羟色胺受体(5-HT1A、5-HT1B或5-HT2C)的破坏都没有导致心血管缺陷。在这项研究中，我们研究了5-HT2B受体突变小鼠，以评估5-羟色胺在心脏结构和功能中的可能作用。方法和结果-我们通过同源重组获得了G(Q)偶联的5-HT2B受体缺失小鼠。存活下来的5-HT2B受体突变小鼠表现为心肌病，由于心肌细胞的数量和大小减少，导致心肌质量损失。这种表型是心肌细胞固有的。5-HT2B受体突变的脑室表现出收缩元素的扩张和异常组织，包括Z-条纹增大和N-钙粘素下调。超声心动图和心电图均证实成年5-HT2B受体突变小鼠存在左室扩大和收缩功能下降。结论5-HT2B受体突变可导致心肌病而不伴有肥厚和间盘破坏。5-HT2B受体通过调节N-钙粘附素的表达，使细胞骨架组装到膜结构上。这些结果首次构成了5-羟色胺通过5-HT2B受体调节心脏结构和功能的强有力的遗传学证据。
Background-Identification of factors regulating myocardial structure and function is important to understand the pathogenesis of heart disease. Because little is known about the molecular mechanism of cardiac functions triggered by serotonin, the link between downstream signaling circuitry of its receptors and the heart physiology is of widespread interest. None of the serotonin receptor (5-HT1A, 5-HT1B, or 5-HT2C) disruptions in mice have resulted in cardiovascular defects. In this study, we examined 5-HT2B receptor-mutant mice to assess the putative role of serotonin in heart structure and function.Methods and Results-We have generated G(q)-coupled 5-HT2B receptor-null mice by homologous recombination. Surviving 5-HT2B receptor-mutant mice exhibit cardiomyopathy with a loss of ventricular mass due to a reduction in number and size of cardiomyocytes. This phenotype is intrinsic to cardiac myocytes. 5-HT2B receptor-mutant ventricles exhibit dilation and abnormal organization of contractile elements, including Z-stripe enlargement and N-cadherin downregulation. Echocardiography and ECG both confirm the presence of left ventricular dilatation and decreased systolic function in the adult 5-HT2B receptor-mutant mice.Conclusions-Mutation of 5-HT2B receptor leads to a cardiomyopathy without hypertrophy and a disruption of intercalated disks. 5-HT2B receptor is required for cytoskeleton assembly to membrane structures by its regulation of N-cadherin expression. These results constitute, for the first time, strong genetic evidence that serotonin, via the 5-HT2B receptor, regulates cardiac structure and function.