title: Genetic deletion of MAO-A promotes serotonin-dependent ventricular hypertrophy by pressure overload.
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 microM vs. 24.0+/-0.9 microM in KO and WT mice, respectively). Cardiac 5-HT(2A), but not 5-HT(2B) 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-HT(2A) receptors in ventricular remodeling in MAO-A KO mice, we administered the 5-HT(2A) 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-HT(2A) receptors.
authors.affiliation: INSERM, U858,Toulouse, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Lairez
authors.forename: Denis
authors.initials: D
authors.lastname: Calise
authors.forename: Pascale
authors.initials: P
authors.lastname: Bianchi
authors.forename: Catherine
authors.initials: C
authors.lastname: Ordener
authors.forename: Odile
authors.initials: O
authors.lastname: Spreux-Varoquaux
authors.forename: Céline
authors.initials: C
authors.lastname: Guilbeau-Frugier
authors.forename: Ghislaine
authors.initials: G
authors.lastname: Escourrou
authors.forename: Isabelle
authors.initials: I
authors.lastname: Seif
authors.forename: Jérôme
authors.initials: J
authors.lastname: Roncalli
authors.forename: Nathalie
authors.initials: N
authors.lastname: Pizzinat
authors.forename: Michel
authors.initials: M
authors.lastname: Galinier
authors.forename: Angelo
authors.initials: A
authors.lastname: Parini
authors.forename: Jeanne
authors.initials: J
authors.lastname: Mialet-Perez
mesh_terms: D000818:Animals; D001011:Aorta / Q000473:pathology; D001794:Blood Pressure / Q000187:drug effects; D006332:Cardiomegaly / Q000000981:diagnostic imaging / Q000201:enzymology* / Q000473:pathology* / Q000503:physiopathology; D005355:Fibrosis; D005464:Fluorobenzenes / Q000008:administration & dosage / Q000494:pharmacology; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000187:drug effects; D006352:Heart Ventricles / Q000000981:diagnostic imaging / Q000201:enzymology / Q000473:pathology* / Q000503:physiopathology; D007650:Ketanserin / Q000008:administration & dosage / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D008995:Monoamine Oxidase / Q000235:genetics* / Q000378:metabolism; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology; D011312:Pressure; D011985:Receptors, Serotonin / Q000235:genetics / Q000378:metabolism; D012701:Serotonin / Q000097:blood / Q000378:metabolism*; D013312:Stress, Physiological / Q000187:drug effects; D014463:Ultrasonography
chemical_list: D005464:Fluorobenzenes; D010880:Piperidines; D011985:Receptors, Serotonin; D012701:Serotonin; D007650:Ketanserin; D008995:Monoamine Oxidase; C079049:volinanserin