A novel role for serotonin in heart

Congenital heart disease is a major cause of disability and morbidity, often initiated by both environmental components and genetic susceptibility. Identification of factors controlling myocardial differentiation and proliferation is of great importance for understanding the pathogenesis of congenital heart diseases. Several lines of evidence suggest that serotonin [5-hydroxytryptamine (5-HT)] regulates cardiovascular functions during embryogenesis and adulthood. However, the molecular mechanism by which 5-HT regulates embryonic development of heart and cardiovascular functions remained unknown until recently. Inactivation of the 5-HT2B receptor (5-HT2BR) gene leads to embryonic and neonatal death due to the following defects in the heart: (a) 5-HT2BR mutant embryos exhibit a lack of trabeculae in the heart and a reduction in the expression levels of a tyrosine kinase receptor; called ErbB-2, leading to raid-gestation lethality. These in vivo data suggest that the Gq-coupled 5-HT2BR uses the signaling pathway of the tyrosine kinase receptor ErbB-2 for cardiac differentiation. (b) Newborn 5-HT2BR mutant mice exhibit cardiac dilation resulting from contractility deficits and structural deficits at the intercellular junctions between cardiomyocytes. (c) In adult 5-HT2BR mutant mice, echocardiography and electrocardiography confirm the presence of left ventricular dilation and decreased systolic function. These results constitute the first genetic evidence that 5-HT via the 5-HT2BR, regulates differentiation and proliferation during development as well as cardiac structure and function in adults. (C) 2001, Elsevier Science Inc.