Ablation of serotonin 5-HT 2B receptors in mice leads to abnormal cardiac structure and function

Canan G Nebigil (1) , Pierre Hickel (1) , Nadia Messaddeq (1) , Jean-Luc Vonesch (1) , Marie P Douchet (2) , Laurent Monassier (3) , Katalin György (4) , Rachel Matz (4) , Ramaroson Andriantsitohaina (5) , Philippe Manivet (6) , Jean-Marie Launay (7) , Luc Maroteaux (1)

1 IGBMC - Institut de génétique et biologie moléculaire et cellulaire
2 UNISTRA - Université de Strasbourg
3 Régulation nerveuse de la fonction cardiovasculaire
4 PPCICM - Pharmacologie et physico-chimie des interactions cellulaires et moléculaires
5 SOPAM - Stress Oxydant et Pathologies Métaboliques
6 Hôpital Lariboisière
7 BioCANVAS / U942 - Biomarqueurs CArdioNeuroVASCulaires

Background-Identification of factors regulating myocardial structure and function is important to understand the pathogenesis of heart disease. Since 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 Gq-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 Zstripe enlargement and N-cadherin down regulation. Echocardiography and electrocardiography 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 discs. 5-HT 2B receptor is required for cytoskeleton assembly to membrane structures by regulating the N-cadherin expression. These results constitute, for the first time, strong genetic evidence that serotonin, via 5-HT 2B receptor, regulates cardiac structure and function.

Mots clés: Cardiomyopathy; Cell adhesion molecules; Genetics; serotonin

Domaines: Cardiologie et système cardiovasculaire; Biologie moléculaire

Canan G Nebigil, Pierre Hickel, Nadia Messaddeq, Jean-Luc Vonesch, Marie P Douchet, et al.. Ablation of serotonin 5-HT 2B receptors in mice leads to abnormal cardiac structure and function. Circulation, 2001, 103 (24), pp.2973-2979. ⟨10.1161/01.cir.103.24.2973⟩. ⟨hal-03721232⟩