Genetic deletion of MAO-A promotes serotonin-dependent ventricular hypertrophy by pressure overload |
| |
Authors: | Olivier Lairez Denis Calise Pascale Bianchi Catherine Ordener Odile Spreux-Varoquaux Céline Guilbeau-Frugier Ghislaine Escourrou Isabelle Seif Nathalie Pizzinat Michel Galinier Angelo Parini Jeanne Mialet-Perez |
| |
Institution: | a INSERM; U858; F-31432 Toulouse, France b Université de Toulouse; UPS; Institut de Médecine Moléculaire de Rangueil; CHU de Toulouse; IFR31, F-31432 Toulouse, France c Université Versailles St-Quentin-en-Yvelines, Pharmacologie, Faculté de Médecine Paris-Ile de France-Ouest, 78000, France d Service de Biologie, Unité de Pharmacologie, Centre Hospitalier de Versailles, Le Chesnay, 78157, France e Université Paris-Sud; EA3544, Châtenay-Malabry, France |
| |
Abstract: | The potential role of serotonin (5-HT) in cardiac function has generated much interest in recent years. In particular, the need for a tight regulation of 5-HT to maintain normal cardiovascular activity has been demonstrated in different experimental models. However, it remains unclear how increased levels of 5-HT could contribute to the development of cardiac hypertrophy. Availability of 5-HT depends on the mitochondrial enzyme monoamine oxidase A (MAO-A). Therefore, we investigated the consequences of MAO-A deletion on ventricular remodeling in the model of aortic banding in mice. At baseline, MAO-A deletion was associated with an increase in whole blood 5-HT (39.4 ± 1.9 μM vs. 24.0 ± 0.9 μM in KO and WT mice, respectively). Cardiac 5-HT2A, but not 5-HT2B receptors were overexpressed in MAO-A KO mice, as demonstrated by real-time PCR and Western-blot experiments. After aortic banding, MAO-A KO mice demonstrated greater increase in heart wall thickness, heart to body weight ratios, cardiomyocyte cross-section areas, and myocardial fibrosis compared to WT. Exacerbation of hypertrophy in KO mice was associated with increased amounts of 5-HT in the heart. In order to determine the role of 5-HT and 5-HT2A receptors in ventricular remodeling in MAO-A KO mice, we administered the 5-HT2A receptor antagonists ketanserin (1 mg/kg/day) or M100907 (0.1 mg/kg/day) during 4 weeks of aortic banding. Chronic administration of these antagonists strongly prevented exacerbation of ventricular hypertrophy in MAO-A KO mice. These results show for the first time that regulation of peripheral 5-HT by MAO-A plays a role in ventricular remodeling via activation of 5-HT2A receptors. |
| |
Keywords: | 5-HT MAO-A Hypertrophy Fibrosis Remodeling 5-HT2A |
本文献已被 ScienceDirect 等数据库收录! |
|