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-HT(2B) receptor (5-HT(2B)R) gene leads to embryonic and neonatal death due to the following defects in the heart: (a) 5-HT(2B)R 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 mid-gestation lethality. These in vivo data suggest that the Gq-coupled 5-HT(2B)R uses the signaling pathway of the tyrosine kinase receptor ErbB-2 for cardiac differentiation. (b) Newborn 5-HT(2B)R mutant mice exhibit cardiac dilation resulting from contractility deficits and structural deficits at the intercellular junctions between cardiomyocytes. (c) In adult 5-HT(2B)R 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-HT(2B)R, regulates differentiation and proliferation during development as well as cardiac structure and function in adults.
Nebigil
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CG
Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS, INSERM, Université L. Pasteur de Strasbourg, Illkirch, France.
Maroteaux
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D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000209:etiology / Q000503:physiopathology; D005544:Forecasting; D020868:Gene Silencing; D006321:Heart / Q000196:embryology* / Q000503:physiopathology; D006330:Heart Defects, Congenital / Q000235:genetics; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D011985:Receptors, Serotonin / Q000235:genetics*; D012701:Serotonin / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction
D011985:Receptors, Serotonin; D012701:Serotonin