Ablation of Serotonin 5-HT2BReceptors in Mice Leads to Abnormal Cardiac Structure and Function

• DOI: 10.1161/01.cir.103.24.2973
• Publication Date: 2012-06-12T00:09:32Z
• Authors: Canan G. Nebigil; Pierre Hickel; Nadia Messaddeq; Jean-Luc Vonesch; Marie P. Douchet; Laurent Monassier; Katalin György; Rachel Matz; Ramaroson Andrian...; Philippe Manivet; Jean-Marie Launay; Luc Maroteaux
• Keywords: MESH: Organ Size; Gene Expression; MESH: Adrenergic beta-Agonists; Cell Count; Cell Separation; [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology; MESH: Cadherins; Congenital; Electrocardiography; Heart Rate; MESH: Receptors; MESH: Animals; 5-HT2B; MESH: Heart Rate; MESH: Cell Size; Cytoskeleton; 0303 health sciences; Cell adhesion molecules; Adrenergic beta-Agonists; Cadherins; Molecular Biology/Molecular biology; serotonin; [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system; 3. Good health; Echocardiography; Female; Drug; Cardiomyopathies; Heart Defects, Congenital; MESH: Hemodynamics; MESH: Myocardium; MESH: Gene Expression; Cardiomyopathy; Knockout; Heart Ventricles; MESH: Dose-Response Relationship; 610; MESH: Phenotype; MESH: Cell Separation; 03 medical and health sciences; MESH: Sex Factors; [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system; MESH: Cytoskeleton; MESH: Heart Defects; Genetics; Animals; MESH: Mice; Cell Size; MESH: In Vitro Techniques; Dose-Response Relationship, Drug; MESH: Cell Count; MESH: Receptor; Body Weight; Hemodynamics; Newborn; MESH: Male; MESH: Body Weight; MESH: Electrocardiography; MESH: Cardiomyopathies; Animals, Newborn; [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry; MESH: Biomarkers; MESH: Echocardiography; MESH: Heart Ventricles; MESH: Female; Biomarkers

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-HT1A, 5-HT1B, or 5-HT2C) disruptions in mice have resulted in cardiovascular defects. In this study, we examined 5-HT2Breceptor–mutant mice to assess the putative role of serotonin in heart structure and function.Methods and Results—We have generated Gq-coupled 5-HT2Breceptor–null mice by homologous recombination. Surviving 5-HT2Breceptor–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-HT2Breceptor–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-HT2Breceptor–mutant mice.Conclusions—Mutation of 5-HT2Breceptor leads to a cardiomyopathy without hypertrophy and a disruption of intercalated disks. 5-HT2Breceptor 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-HT2Breceptor, regulates cardiac structure and function.