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(Circulation. 2001;103:2973.)
© 2001 American Heart Association, Inc.

Basic Science Reports

Ablation of Serotonin 5-HT_2B Receptors in Mice Leads to Abnormal Cardiac Structure and Function

Canan G. Nebigil, PharmD, PhD; Pierre Hickel, BS; Nadia Messaddeq, PhD; Jean-Luc Vonesch, PhD; Marie P. Douchet, MD; Laurent Monassier, MD, PhD; Katalin György, PhD; Rachel Matz, PhD; Ramaroson Andriantsitohaina, PhD; Philippe Manivet, PharmD; Jean-Marie Launay, PharmD, PhD; Luc Maroteaux, PhD

From the Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS, INSERM, Université de Strasbourg, Illkirch (C.G.N., P.H., N.M., J.L.V., L. Maroteaux); the Faculté de Médecine, Strasbourg (M.P.D., L. Monassier); CNRS, Faculté de Pharmacie, Illkirch (K.G., R.M., R.A.); and Centre de Recherches Claude Bernard, Service de Biochimie, Hôpital Lariboisière, Paris (P.M., J.-M.L.), France.

Correspondence to Luc Maroteaux, IGBMC, BP 163, 67404 Illkirch Cedex, France. E-mail lucm{at}igbmc.u-strasbg.fr

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.

Key Words: cardiomyopathy • cell adhesion molecules • genetics • serotonin

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