Abstract 2959: Pharmacological and Genetic Inhibition of Monoamine Oxidase A Prevents Enhanced Norepinephrine Catabolism and Heart Failure After Pressure Overload
Monoamine oxidases (MAO) are mitochondrial enzymes that catabolize pro-hypertrophic neurotransmitters such as norepinephrine (NE), generating hydrogen peroxide in this process. In heart failure (HF) subjects, reactive oxygen species (ROS) are in excess and catecholamine cycling is altered. Hence, MAO activity may contribute to maladaptive hypertrophy and its transition to heart failure. To test this, we used an in vitro and in vivo approach. Stimulating rat neonatal myocytes with NE (2 hrs) triggered MAO-A activity and led to increased mitochondrial ROS production. Prolonged incubation with NE (24 hrs) determined an increase in cell size, expression of fetal genes and induction of maladaptive hypertrophy mediators (i.e. NFAT3/NFAT4 genes). These changes were effectively blunted (−50%) by the specific MAO-A inhibitor clorgyline (CLO). The role of MAO-A in in vivo CHF was assessed in mice with transverse aortic constriction (TAC). MAO-A mediated NE catabolism was 3-fold higher in hearts after 6 weeks of TAC (p<0.05). These hearts were dilated and functionally impaired (−52% in FS by echo), displaying altered redox balance (3-fold rise in MDA levels), increased apoptotic rate and a marked (4-fold) reduction in the NE transporter (NET) protein expression (p<0.01). The latter hints to impaired neuronal NE re-uptake/storage and higher NE availability at extraneuronal sites in TAC hearts. CLO reversed fetal gene re-programming, preserved LV structure/function while rescuing NET content to control levels. Specific involvement of MAO-A was validated using dominant-negative MAO-A mice (MAO-Aneo). Unlike their WT littermates, MAO-Aneo mice displayed preserved LV dimensions (EDV was 25.7±3.6 vs 41.4±3.3 μl, p<0.005) and LV function (EF: 79±3 vs 53±8 %, p<0.005) after TAC as per pressure-volume analysis, showing also less LV fibrosis. Our data shows that, in addition to adrenergic receptor-dependent mechanisms, enhanced NE availability at myocyte level triggers MAO-A activity, fueling oxidative stress and adverse LV remodeling/dysfunction. At neuronal level, MAO-A likely affects NET function and NE re-cycling. Thus, inhibiting MAO-A activity at both sites may be clinically relevant, improving LV function and countering remodeling in HF subjects.
This research has received full or partial funding support from the American Heart Association, Mid-Atlantic Affiliate (Maryland, North Carolina, South Carolina, Virginia & Washington, DC).