Why the study?
Little is known about the molecular mechanisms by which serotonin receptors regulate cardiac structure and function, particularly the role of 5-HT(2B) receptors.
Does ablation of serotonin 5-HT2B receptors lead to abnormal cardiac structure and function in mice?
Does ablation of serotonin 5-HT2B receptors lead to abnormal cardiac structure and function in mice?
Ablation of the 5-HT2B receptor in mice leads to cardiomyopathy, providing genetic evidence that serotonin regulates cardiac structure and function.
Mouse 5-HT2B ablation causing cardiomyopathy cautions against human receptor targeting; leaves open serotonin's therapeutic relevance in heart disease.
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-HT(1A), 5-HT(1B), or 5-HT(2C)) disruptions in mice have resulted in cardiovascular defects. In this study, we examined 5-HT(2B) 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-HT(2B) receptor-null mice by homologous recombination. Surviving 5-HT(2B) 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-HT(2B) 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-HT(2B) receptor-mutant mice. CONCLUSIONS: Mutation of 5-HT(2B) receptor leads to a cardiomyopathy without hypertrophy and a disruption of intercalated disks. 5-HT(2B) 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-HT(2B) receptor, regulates cardiac structure and function.
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Nebigil et al. (2001) studied this question.
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