Genetic deletion of MAO-A promotes serotonin-dependent ventricular hypertrophy by pressure overload. - Archive ouverte HAL Access content directly
Journal Articles Journal of Molecular and Cellular Cardiology Year : 2009

Genetic deletion of MAO-A promotes serotonin-dependent ventricular hypertrophy by pressure overload.

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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.
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Dates and versions

inserm-00409926 , version 1 (14-08-2009)

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Olivier Lairez, Denis Calise, Pascale Bianchi, Catherine Ordener, Odile Spreux-Varoquaux, et al.. Genetic deletion of MAO-A promotes serotonin-dependent ventricular hypertrophy by pressure overload.. Journal of Molecular and Cellular Cardiology, 2009, 46 (4), pp.587-95. ⟨10.1016/j.yjmcc.2008.12.017⟩. ⟨inserm-00409926⟩
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