In the prior study, even the WT mice showed little dilation and preserved function. prevents these changes, and also reverses fetal gene re-programming, metalloproteinase and caspase-3 activation as well as myocardial apoptosis. The specific A-385358 role of MAO-A was further tested in mice expressing a dominant-negative MAO-A (MAO-Aneo), which were more guarded against pressure overload than their wild type littermates. == Conclusions == In addition to adrenergic receptor-dependent mechanisms, enhanced MAO-A activity coupled with increased intramyocardial NE availability results in increased ROS generation, contributing to maladaptive remodeling and LV dysfunction in hearts subjected to chronic stress. Keywords:MAO-A, congestive heart failure, oxidative stress, catecholamines, serotonin, NET == Introduction == Hemodynamic overload prospects to increased cardiac mass and cardiomyocyte volume associated with characteristic changes in gene and protein expression. This initial compensatory hypertrophy is usually replaced by progressive structural/functional cardiac remodeling involving alterations in extracellular matrix (ECM) composition, myocardial energetics, Ca2+cycling, and myocyte viability1-4. Reactive oxygen species (ROS) contribute to each of these abnormalities5-10, but relevant sources of ROS remain to be fully defined. This is important, as recent studies suggest that specific targeting of ROS sources provides a more effective therapy for heart remodeling11. Monoamine oxidases (MAO) are mitochondrial flavoenzymes which catalyze oxidative deamination of catecholamines (CA) and biogenic amines such as serotonin. During this process they generate hydrogen peroxide (H2O2), and thus can potentially be a source of oxidative Mouse monoclonal to TIP60 stress in the heart, particularly under stress conditions. Yet, while the role of MAO in terminating neurotransmitter signaling in the brain is well established12, little is known about its modulation of cardiac morphology and function. MAO exist in two isoforms, MAO-A and B, with unique substrate and inhibitor sensitivity12. MAO-A, in particular, is present in the myocardium of several species from humans to rodents13-15, where it principally catabolizes serotonin, norepinephrine (NE) and epinephrine. All these monoamine neurotransmitters have major functional implications in the heart, especially in the modulation of cardiac inotropy. A role for MAO-A and serotonin in ischemic/reperfused myocardium has been delineated showing that inhibiting MAO-A countermands oxidative stress, neutrophil accumulation and mitochondria-dependent cell death16. Yet, the involvement of MAO-A and its impact on neurotransmitter availability in congestive heart failure (CHF) remains poorly defined, though one could speculate that this is usually the type of setting wherein MAO-A might be chiefly at play. CHF is accompanied by enhanced sympathetic firmness17, extra circulating CA A-385358 such as NE18, and increased oxidative stress19. In such situations, MAO-A may be up-regulated, generating greater amounts of H2O2thus exacerbating disease progression. Here, we first decided whether cardiomyocyte (both neonatal and adult) exposure to NE is coupled to augmented MAO-A expression/activity which in turn regulates a hypertrophic response linked to the generation of intracellular ROS. Adrenergic receptor impartial signaling was assessed using the MAO substrate tyramine. Second, we hypothesized that prolonged hemodynamic stress imposed byin vivopressure overload prospects to extra CA (and/or serotonin) presence at the myocyte surface resulting in increased sarcolemmal transport via extraneuronal monoamine transporter20,21(EMT), thus enhancing substrate availability for intramyocyte MAO-A activity. To test this, we subjected mice to transverse aortic constriction (TAC), in absence and presence of the highly selective MAO-A inhibitior clorgyline22, and in mice expressing a dominant unfavorable MAO-A (MAO-Aneo). Here we show that NE triggers ROS and myocyte hypertrophy in part by a MAO-A dependent mechanismin vitro.In vivo, NE catabolism and ROS production are markedly up-regulated in pressure overloaded hearts and both effects are ameliorated by inhibiting MAO-A activity to suppress cardiac decompensation with pressure-overload. == Methods == == Animals == For pharmacological studies, male C57BL/6 mice (n=30, 9-11 weeks aged) were used and clorgyline was administered using saline as vehicle (1 mg/kg/day, i.p.). For experiments employing genetically altered mice, MAO-Aneomice and their wild type (WT) littermates in 129/Sv background were used (n=30). The Johns Hopkins University or college Institutional Animal Care and Use Committee approved A-385358 all animal experiments. == Statistics == All values are expressed as meanSEM. Comparison between groups was performed by one-way or two-way ANOVA, followed by a Tukey’s post-hoc.