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Serotonin effects on cardiac hypertrophy, senescence, and failure are dependent either on activation of specific receptors or serotonin uptake and serotonin degradation by monoamine oxidases (MAOs). Receptor-dependent effects are specific for serotonin, but MAO-dependent effects are nonspecific as MAOs also metabolize other substrates such as catecholamines. Our study evaluates the role of MAO-A in serotonin- and norepinephrine-dependent cell damage. Experiments were performed in vivo to study the regulation of <i>MAOA</i> and <i>MAOB</i> expression and in vitro on isolated cultured adult rat ventricular cardiomyocytes (cultured for 24 h) to study the function of MAO-A. <i>MAOA</i> but not <i>MAOB</i> expression increased in maladaptive hypertrophic stages. Serotonin and norepinephrine induced morphologic cell damage (loss of rod-shaped cell structure). However, MAO-A inhibition suppressed serotonin-dependent but not norepinephrine-dependent damages. Serotonin but not norepinephrine caused a reduction in cell shortening in nondamaged cells. Serotonin induced mitochondria-dependent oxidative stress. In vivo, <i>MAOA</i> was induced during aging and hypertension but the expression of the corresponding serotonin uptake receptor (<i>SLC6A4</i>) was reduced and enzymes that reduce either oxidative stress (<i>CAT</i>) or accumulation of 5-hydroxyindolacetaldehyde (<i>ALDH2</i>) were induced. In summary, the data show that MAO-A potentially affects cardiomyocytes’ function but that serotonin is not necessarily the native substrate.