p53-PGC-1α Pathway Mediates Oxidative Mitochondrial Damage and Cardiomyocyte Necrosis Induced by Monoamine Oxidase-A Upregulation: Role in Chronic Left Ventricular Dysfunction in Mice

Abstract

Aims: Oxidative stress and mitochondrial dysfunction participate together in the development of heart failure (HF). mRNA levels of monoamine oxidase-A (MAO-A), a mitochondrial enzyme that produces hydrogen peroxide (H 2 O 2 ), increase in several models of cardiomyopathies. Therefore, we hypothesized that an increase in cardiac MAO-A could cause oxidative stress and mitochondrial damage, leading to cardiac dysfunction. In the present study, we evaluated the consequences of cardiac MAO-A augmentation on chronic oxidative damage, cardiomyocyte survival, and heart function, and identified the intracellular pathways involved. Results: We generated transgenic (Tg) mice with cardiac-specific MAO-A overexpression. Tg mice displayed cardiac MAO-A activity levels similar to those found in HF and aging. As expected, Tg mice showed a significant decrease in the cardiac amounts of the MAO-A substrates serotonin and norepinephrine. This was associated with enhanced H 2 O 2 generation in situ and mitochondrial DNA oxidation. As a consequence, MAO-A Tg mice demonstrated progressive loss of cardiomyocytes by necrosis and ventricular failure, which were prevented by chronic treatment with the MAO-A inhibitor clorgyline and the antioxidant N-acetyl-cystein. Interestingly, Tg hearts exhibited p53 accumulation and downregulation of peroxisome proliferator-activated receptor-c coactivator-1a (PGC-1a), a master regulator of mitochondrial function. This was concomitant with cardiac mitochondrial ultrastructural defects and ATP depletion. In vitro, MAO-A adenovirus transduction of neonatal cardiomyocytes mimicked the results in MAO-A Tg mice, triggering oxidative stress-dependent p53 activation, leading to PGC-1a downregulation, mitochondrial impairment, and cardiomyocyte necrosis. Innovation and Conclusion: We provide the first evidence that MAO-A upregulation in the heart causes oxidative mitochondrial damage, p53-dependent repression of PGC-1a, cardiomyocyte necrosis, and chronic ventricular dysfunction. Antioxid. Redox Signal. 18, 5-18.

Monoamine oxidase‐A is a novel driver of stress‐induced premature senescence through inhibition of parkin‐mediated mitophagy

“…Tyr treatment induced a dose‐dependent increase in ROS production in cardiomyocytes (Figure 2e). On one hand, we found that above the concentration of 250 µM of Tyr, primary cardiomyocytes underwent cell death, consistent with our previous findings (Villeneuve et al, 2013) (Figure 2f). On the other hand, at doses of 100, 50 and 10 µM, no cytotoxicity was observed with Tyr up to 72 hr (Figure 2f).…”

“…These particular responses might depend on the cell type and on the amount of H 2 O 2 , which is known to drive dose‐dependent cellular effects (Duan, Duan, Zhang, & Tong, 2005; Giorgio et al, 2007). During cardiac ischaemia‐reperfusion injury, where high levels of MAO substrates are released, and in the hearts of transgenic mice overexpressing MAO‐A, cell apoptosis and necrosis are preferentially activated together with the lysosomal alteration‐induced blockade of the autophagic flux (Bianchi et al, 2005; Santin et al, 2016; Villeneuve et al, 2013). Here, we demonstrate that chronic sublethal doses of H 2 O 2 produced by MAO‐A in response to its endogenous (NE) or exogenous (Tyr) substrates can recapitulate all the features of senescence.…”

“…Here, we demonstrate that chronic sublethal doses of H 2 O 2 produced by MAO‐A in response to its endogenous (NE) or exogenous (Tyr) substrates can recapitulate all the features of senescence. This could have particular relevance in cardiac ageing, where MAO‐A is likely to be chronically activated due to: (a) sympathetic activation and enhanced release of norepinephrine from adrenergic nerves (Santulli & Iaccarino, 2016); and (b) overexpression of MAO‐A in the ageing heart (as shown in Figure 1a,b) or in age‐associated cardiac diseases (Manni et al, 2016; Villeneuve et al, 2013). In addition, the role of MAO‐A in senescence could be extended to different cell types, since MAO‐A has been characterized in many proliferative cells, such as fibroblasts and bone marrow mesenchymal stem cells, where its expression was significantly increased during ageing (Edelstein & Breakefield, 1986; Trouche et al, 2010).…”

“…In the heart, MAO‐A has been demonstrated to be an important source of oxidative stress in acute and chronic pathological conditions (Bianchi et al, 2005; Kaludercic et al, 2010). In particular, cardiac overexpression of MAO‐A drives oxidative stress and mitochondrial damage, leading to cell death and heart failure (Kaludercic, Mialet‐Perez, Paolocci, Parini, & Di Lisa, 2014; Villeneuve et al, 2013). Notably, all these effects are observed with high levels of MAO‐A activation, and it is well‐established that depending on its concentration, H 2 O 2 can have multiple dose‐dependent cellular responses, ranging from proliferation to necrosis (Giorgio, Trinei, Migliaccio, & Pelicci, 2007).…”

“…Notably, all these effects are observed with high levels of MAO‐A activation, and it is well‐established that depending on its concentration, H 2 O 2 can have multiple dose‐dependent cellular responses, ranging from proliferation to necrosis (Giorgio, Trinei, Migliaccio, & Pelicci, 2007). p53 is one of the main effectors of the MAO‐A/H 2 O 2 axis (Villeneuve et al, 2013), which is at the crossroad of numerous signalling pathways and, depending on the extent of damage, can initiate DNA repair, senescence or cell death (Green & Kroemer, 2009). These observations, together with the fact that MAO‐A expression increases in the ageing heart (Maurel et al, 2003), led us to investigate whether a chronic increase in H 2 O 2 through persistent MAO‐A activation could drive senescence in cardiac cells.…”