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

Genetic deletion of MAO-A promotes serotonin-dependent ventricular hypertrophy by pressure overload,10.1016/j.yjmcc.2008.12.017,Journal of Molecular a

Genetic deletion of MAO-A promotes serotonin-dependent ventricular hypertrophy by pressure overload   (Citations: 7)
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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.
Journal: Journal of Molecular and Cellular Cardiology - J MOL CELL CARDIOL , vol. 46, no. 4, pp. 587-595, 2009
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